Pyrimidine derivatives and processes for the preparation thereof

ABSTRACT

The present invention relates to novel pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts thereof which possess an excellent anti-secretory activity, pharmaceutical compositions containing the same as an active ingredient, their novel intermediates, and processes for the preparation thereof wherein: when A is piperidin- 1 -yl or —NH—B, wherein B is C 3 -C 4  alkyl, C 3 -C 4  alkenyl, C 3 -C 7  cycloalkyl, C 1 -C 3  alkoxyethyl, phenylethl which may be substituted or unsubstituted, 3-trifluoromethylphenylmethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl, R 1  is hydrogen or methyl; and R 2 , R 3 , R 4  and R 5  are hydrogen; or when A is a group of formula (II); when R 1  is hydroxymethyl or C 1 -C 3  alkoxymethyl, R 2 , R 3 , R 4 , R 5  and R 6  are hydrogen; and R 7  is hydrogen or halogen; or when R 1  is hydrogen or methyl, R 7  is hydrogen or halogen; and one or two of R 2 , R 3 , R 4 , R 5  and R 6  is hydroxy, methoxy, or a group of formula (III) wherein Z is C 1 -C 4  alkyl, substituted or unsubstituted C 1 -C 4  alkenyl, cyloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl, piperidinomethyl, 4-substituted-piperazinomethyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl, thiophen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or —CHR 8 NHR 9 , wherein R 8  is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxycarbonylmethyl, carbamolymethyl, carbamoylethyl, or 1-benzylimidazol-4-ylmethyl and R 9  is hydrogen or t-butoxycarbonyl; and the others are hydrogen or methyl.

This is a 371 of PCT/KR98/00058 filed Feb. 25, 1999.

FIELD OF THE INVENTION

The present invention relates to novel pyrimidine derivatives orpharmaceutically acceptable salts thereof which possess an excellentanti-secretory activity, pharmaceutical compositions containing same asan active ingredient, their novel intermediates, and processes for thepreparation thereof.

BACKGROUND OF THE INVENTION

For the treatment of peptic ulcer disease, various drugs such asantacid, anticholinergic agent, H₂-receptor antagonist and proton pumpinhibitor have been used. The advent of omeprazole useful as a protonpump inhibitor has rekindled research activities in this field.

However, it has been pointed out that the proton pump inhibition byomeprazole is irreversible, which may induce side effects. Accordingly,various attempts to develop a reversible proton pump inhibitor are beingactively made. For example, European Patent Nos. 322133 and 404322disclose quinazoline derivatives, European Patent No. 259174 describesquinoline derivatives, and WO 91/18887 offers pyrimidine derivatives, asa reversible proton pump inhibitor. Further, the present inventors havealso reported quinazoline derivatives in WO 94/14795 and pyrimidinederivatives in WO 96/05177.

SUMMARY OF THE INVENTION

The present inventors have carried out extensive research to develop areversible proton pump inhibitor with improved efficacy, and as a resulthave discovered that pyrimidine derivatives having a substitutedtetrahydroisoquinoline group at 4-position of the pyrimidine nucleus orsubstituents at the 2-, 5-, or 6-positioni of the pyrirnidine nucleusexhibit excellent proton pump inhibition effects and possess the abilityto attain a reversible proton pump inhibition.

Accordingly, it is a primary object of the present invention to providenovel pyrimidine derivatives having a substituted tetraydroisoquinolinegroup at 4-position of the pyrimidine nucleus or substituents at the 2-,5-, or 6-position of the pyrirnidine nucleus, or pharmaceuticallyacceptable salts thereof.

It is another object of the present invention to provide processes forpreparing said compounds.

It is a further object of the present invention to providepharmaceutical compositions for treating peptic ulcer containing thesame as active ingredients. it is still another object of the, inventionto provide novel intermediate compounds useful for the preparation ofthe novel pyrimidine derivatives.

In accordance with on aspect of the present invention, there areprovided novel pyrimidine derivatives of formula (I) or pharmaceuticallyacceptable salts thereof:

wherein:

when A is piperidin-1-yl or —NH—B, wherein B is C₃-C₄ alkenyl, C₃-C₇cycloalkyl, C₁-C₃ alkoxyethyl, phenylethyl which may be substituted orunsubstituted, 3-trifluoromethylphenylmethyl, 1-naphthyl-methyl,4-methylthiazol-2-yl or 4-phenylthiazol-2-yl,

R₁ is hydrogen or methyl; and

R₂, R₃, R₄ and R₅ are hydrogen; or

when A is a group of formula (II):

when R₁ is hydroxymethyl or C₁-C₃ alkoxymethyl,

R₂, R₃, R₄, R₅ and R₆ are hydrogen; and

R₇ is hydrogen or halogen; or

when R₁ is hydrogen or methyl,

R₇ is hydrogen or halogen; and

one or two of R₂, R₃, R₄, R₅ and R₆ is hydroxy, methoxy, or a group offormula (III):

wherein Z is C₁-C₄ alkyl, substituted or unsubstituted C₂-C₄ alkenyl,cycloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl,piperidinomethyl, 4-substituted-piperazine-methyl, substituted orunsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl,thiopen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or —CHR₈NHR₉, whereinR₈ is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl,methylthioethyl, benzyloxy-carbonylmethyl, carbamoylmethyl,carbamoylethyl, or 1-benzyl imdazol-4-ylmethyl and R₉ is hydrogen ort-butoxycarbonyl; and the others are hydrogen or methyl.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of formula (I), preferred are the compounds of thefollowing formula (I-1):

wherein R₁ is hydrogen or methyl; and A′ is piperidin-1-yl or —NH—B,wherein B is C₃-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₇ cycloalkyl, C₁-C₃alkoxyethyl, phenylethyl which may be substituted or unsubstituted,3-trifluoromethyl phenylmethyl, 1-naphthylmethyl, 4-methylthiazol-2-ylor 4-phenylthiazol-2-yl.

Among the compounds of the formula (I), also preferred compounds are thecompounds of the following formula (I-2):

wherein R₁ is hydrogen or methyl; R₇ is hydrogen or halogen; one or twoof R₂′, R₃′, R₄′, R₅′ and R₆′ is hydroxy or methoxy and the others arehydrogen or methyl.

Similarly preferred compounds are those of the following formula (I-3)

wherein R₁ is hydrogen or methyl; R₇ is hydrogen or halogen; one or twoof R₂″, R₃″, R₄″, R₅″ and R₆″ is a group of formula (III):

wherein Z is C₁-C₄ alkyl, substituted or unsbstituted C₁-C₄ alkenyl,C₃-C₆ cycloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl,piperidinomethyl, 4-substituted-piperazinomethyl, substituted orunsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl,thiophen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or —CHR₈NHR₉,wherein R₈ is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl,methylthioethyl, benzyloxycarbonylmethyl, carbamoylmethyl,carbamoylethyl, or 1-benzyl imdazol-4-ylmethyl and R₉ is hydrogen ort-butoxycarbonyl; and

the others are hydrogen or methyl.

Similarly preferred compounds are those of the following formula (I-4)

wherein R₁ is hydroxymethyl or C₁-C₃ alkoxymethyl; and R₇ is hydrogen orhalogen.

The pyrimidine derivatives of formula (I) in the present invention mayexist in the form of an optical isomer, (R) or (S), or a mixturethereof. Both types of the isomeric compounds are found to exhibitexcellent anti-secretory activity.

The compounds of the formula (I-1), (I-2), (I-3), and (I-4) may beprepared in accordance with the following methods.

Method for Preparation of the Formula (I-1)

The compound of formula (I-1a) may be prepared by reacting the compound(IV) with A″H in accordance with Scheme 1 described below.

wherein R₁ is hydrogen or methyl; and A″ is piperidin-1-yl or —NH—B,wherein B is C₃-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₇ cycloalkyl, C₁-C₃alkoxyethyl, phenylethyl which may be substituted or unsubstituted,3-trifluoromethylphenylmethyl, or 1-naphthylmethyl.

In the process of Scheme 1, the compound of formula (IV) may be preparedby the same method as described in WO96/05177. The compound of A″H iscommercially available (for example, from Aldrich Co. in U.S.A.).

As shown in Scheme 1, the pyrimidine compounds (IV) are reacted with A″Hin the presence of an appropriate solvent and a base for 2 to 5 hours togive the compounds of formula (I-1a). Suitable solvents for thisreaction may include dimethylformamide, p-dioxane, dimethylsulfoxide,and propyleneglycol. Suitable base for this reaction may includetriethylamine, N,N-dimethylaniline, and pyridine. The reactiontemperature preferably ranges from 80° C. to 140° C.

The compound of formula (I-1b) may be prepared by a process whichcomprises: chlorinating the compound of formula (V) to give a compoundof formula (VI); and reacting the compound of formula (VI) with1-R₁-1,2,3,4-tetrahydroisoquinoline in accordance with Scheme 2described below.

wherein R₁ is hydrogen or methyl; and R₁₀ is methyl or phenyl.

In the process of Scheme 2, the compound of formula (V) may be preparedby using a known process [see, e.g., J. Med. Chem., 33, 543, (1990); andJ. Heterocyclic. Chem., 28, 231 (1991)].

The compound of formula (V) is chlorinated with chlorinating agent, e.g.phosphorous oxychloride, to give a compound of formula (VI). And thenthe compound of formula (VI) is reacted with1-R₁-1,2,3,4-tetrahydroisoquinoline to give compounds of formula (I-1b).

Method for Preparation of the Formula (I-2)

The compound of formula (I-2a) may be prepared by reacting the compound(VII) with a compound of formula (VIII) in accordance with Scheme 3described below.

wherein R₁, R₂′, R₃′, R₅′, R₆′ and R₇ are the same as defined in formula(I-2); and R₄′″ is hydrogen or methyl.

In Scheme 3, the reaction may be accomplished under same conditions,e.g., solvent, base, reaction time, and temperature, as those ofScheme 1. And also, a compound of formula (I-2a) wherein R₅′ is hydroxymay be prepared by the demethylation of the corresponding compound offormula (I-2a) wherein R₅′ is methoxy.

In the process of Scheme 3, the compound of formula (VII) may beprepared in accordance with Scheme 4.

wherein R₁, R₂′, R₃′, R₄′″ and R₅′ are the same as defined in the above.

In the process of Scheme 4, the compounds of formula (IX) and (XI) maybe prepared by using a known process [see, e.g., J. Heterocyclic. Chem.,28, 231 (1991); Org. Synth., Coll. Vol., IV, 638, (1990); and EuropeanPatent No. 230,871].

The compound of formula (IX) is chlorinated with chlorinating agent,e.g. phosphorous oxychloride, to give a compound of formula (X). Andthen the compound of formula (X) is reacted with a compound of formula(XI) to give compounds of formula (VII). In the process of Scheme 4, thecompound of formula (VII) wherein R₅′ is hydroxy is prepared by thedemethylation of the corresponding compound of formula (VII) wherein R₅′is methoxy.

As shown in Scheme 4, the pyrimidine compounds (X) are reacted with acompound of formula (XI) in the presence of an appropriate solvent and abase for 1 to 24 hours to give the compounds of formula (VII). Suitablesolvents for this reaction may include dichloromethane, acetone,acetonitrile, and dimethylformarnmide. Suitable base for this reactionmay include triethylamine, N,N-dimethylaniline, and pyridine. Thereaction temperature preferably ranges from room temperature to 100° C.

The compounds of formula (VII) prepared as above are novel and useful asintermidiates for the preparation of the pyrimidine compounds of formula(I-2a). Therefore, the present invention encompasses, within its scope,the novel compounds of formula (VII) and process for the preparationthereof.

The compound of formula (I-2b) may be prepared from the compound offormula (XII) in accordance with Scheme 5-1 and 5-2 described below.

wherein R₁ and R₇ are the same as defined in formula (I-2); R₂′″, R₃′″,R₅′″ and R₆′″ are hydrogen or methyl, or one of R₂′″, R₃′″, R₅′″ andR₆′″ is hydroxy or methoxy.

The compound of formula (XII) may be prepared by the same method asdescribed in WO96/05177 or WO97/42186.

As shown in Scheme 5-1, the pyrimidine compound (XII) is reacted withp-formaldehyde in formalin solution for 24 hours to give the compoundsof formula (I-2ba). The reaction temperature preferably ranges from 20°C. to 150° C. And also, in Scheme 5-2, the pyrimidine compound (XII) isreacted with chloromethyl methyl ether in a sealed tube to give thecompounds of formula (I-2bb).

Method for Preparation of the Formula (I-3)

The compound of formula (I-3) may be prepared by reacting the compound(XIII) with a compound of formula (XIV) in accordance with

wherein R₁, R₂″, R₃″, R₄″, R₅″, R₆″, R₇ and Z are the same as defined informula (I-3); one or two of R₂″″, R₃″″, R₄″″, R₅″″ and R₆″″ is hydroxyand the others are hydrogen ; and X is halogen or hydroxy.

When X is halogen in Scheme 6, the pyrimidine compounds (XIII) arereacted with a compound of formula (XIV) in the presence of anappropriate solvent and a base for 3 to 24 hours to give the compoundsof formula (I-3). Suitable solvents for this reaction may includedimethylformamide and dichloromethane. Suitable base for this reactionmay include triethylamine and pyridine. The reaction temperaturepreferably ranges from 0° C. to 50° C.

When X is hydroxy in Scheme 6, the pyrimidine compounds (XIII) arereacted with a compound of formula (XIV) in the presence of anappropriate solvent and a coupling agent for 3 to 24 hours to give thecompounds of formula (I-3). Suitable solvents for this reaction mayinclude dimethylformamide and dichloromethane. Suitable coupling agentsfor this reaction may include 1-hydroxybenzotriazole,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and triethylamine. Thereaction temperature preferably ranges from 0° C. to 50° C.

Method for Preparation of the Formula (I-4)

The compound of formula (I-4) may be prepared by reacting the compound(XV) with a compound of formula (XVI) in accordance with Scheme 7described below.

wherein R₁ is hydroxymethyl or C₁-C₃ alkoxymethyl; and R₇ is hydrogen orhalogen.

In Scheme 7, the reaction may be accomplished under same conditions,e.g., solvent, base, reaction time, and temperature, as those of Scheme1.

The compounds of the present invention may be administered, eitherorally or intraperitoneally, in an effective amount ranging from 0.1 to500 mg/kg, preferably from 1.0 to 100 mg/kg, into a subject patient perday.

The present invention further includes, within its scope,pharmaceutically acceptable salts of the compounds of formula (I). Thenon-toxic salts which fall within the scope of the present invention mayinclude inorganic acid salts such as hydrochloride, sulfate, phosphateand nitrate, and organic acid salts such as tartrate, fumarate, citrate,mesylate and acetate.

The pharmaceutically acceptable salts may be prepared in accordance witha known method, e.g., by reacting the compounds of formula (I) with theacids mentioned above in the presence of a solvent, e.g., ethyl alcohol,dichloromethane, ethyl acetate and diethyl ether.

The present invention also includes within its scope pharmaceuticalcompositions comprising one or more of the inventive compounds as anactive ingredient, in association with a pharmaceutically acceptablecarrier, excipient and/or other additives, if necessary. The activeingredient present in the composition may range from 0.1% to 99.9% byweight thereof.

The following Examples are given for the purpose of illustration only,and are not intended to limit the scope of the invention.2-Chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineand2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinewere prepared by the same method as described in WO96/05177.

Preparation 1: Substituted 1,2,3,4-tetrahydroisoquinoline Preparation1-1: 1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline

Step 1: N-(3-methoxyphenylethyl)acetamide

3-methoxyphenethylamine(50 g, 0.33 mol) was dissolved in a soultion ofwater(130 ml), dichloromethane(210 ml) and sodium hydroxide(17.6 g).Acetyl chloride(25.9 ml, 0.36 mol) was added dropwise at a roomtemperature to the mixture solution, which was then stirred for 1 hour.The separated dichloromethane layer was dried over anhydrous magnesiumsulfate and then concentrated under a reduced pressure to give 63.6 g ofthe titled compound.

Step 2: 6-methoxy-1-methyl-3,4-dihydroisoquinoline

A mixture soultion of polyphosphoric acid (61.4 ml, 0.66 mol) andphosphorouspentoxide(28.0 g, 0.2 mol) was heated to 90° C.N-(3-methoxyphenylethyl) acetamide (63.6 g, 0.33 mol) was added to themixture solution and then stirred for 2 hours at 110° C. The reactionmixture was poured into ice water, adjusted to alkali with potassiumhydroxide, and then extracted with ethyl ether. The extract was driedover anhydrous magnesium sulfate and concentrated under a reducespressure. The resulting residue was purified by a silica gel columnchromatography, using a solution of methanol and dichloromethane (1:20)as a eluent, to give 54.0 g of the titled compound.

Step 3: 6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

6-methoxy-1-methyl-3,4-dihydroisoquinoline (54.0 g, 0.31 mmol) was addedto a suspension of sodium borohydride(5.8 g, 138 mmol) in ethanol. Themixture solution was stirred for 1 hour at a room temperature, cooled tobelow 5° C., acidified with diluted hydrochloric acid, adjusted toalkali with sodium hydroxide solution, and then extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous sodium sulfateand concentrated under a reduced pressure to give 45.4 g of the titledcompound.

Preparation 1-2: 7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

Step 1: N-(4-acetoxyphenylethyl)acetamide

The mixture solution of 4-hydroxyphenethylamine(6.86 g, 50 mmol),triethylamine(13.9 ml, 0.1 mol) and dichloromethane(50 ml) was cooled to0° C. Acetylchloride(7.1 ml, 0.1 mol) was added dropwise to the mixturesolution, which was then stirred for 2 hours at a room temperature,washed with 4N-hydrochloric acid, dried over anhydrous magnesiumsulfate, and then concentrated to give 8.6 g of the titled compound.

Step 2: N-(4-hydroxyphenylethyl)acetamide

A solution of sodium hydroxide(2.3 g, 58 mmol) in water(20 ml) wascooled to 0° C. A solution of N-(4-acetoxyphenylethyl)acetamide(6.4 g,29 mmol) in methanol(40 ml) was added dropwise to the soultion, stirredfor 10 minutes, adjusted to pH 1 with hydrochloric acid, and thenextracted 3 times with ethyl acetate. The extract was washed with water,dried over anhydrous magnesium sulfate and concentrated. The resultingoily residue was solidified with ethyl ether, filtered, and dried togive 4.4 g of the titled compound.

Step 3: N-(4-methoxyphenylethyl)acetamide

Potassium carbonate (3.5 g, 25.5 mol) and iodomethane(2.0 ml, 31.9 mmol)was added to a solution of N-(4-hydroxyphenylethyl)acetamide (4.4 g,24.6 mmol) in ethanol(2.4 ml), which was then refluxed for 12 hours. Theresulting solid was filtered and washed with ethanol. The filtrate wasconcentrated to give oily residue, which was diluted with ethyl acetateand washed with water. The separated organic layer was concentrated andthe resulting solid was suspended in ethylether, filtered, and dried togive 2.9 g of the titled compound.

Step 4: 7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

The same procedures as in Step 2 and 3 of Preparation 1-1 were repeatedusing N-(4-methoxyphenylethyl)acetamide (2.9 g, 14.9 mmol) to afford0.96 g of the titled compound.

Preparation 1-3: 5-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

The same procedures as in Preparation 1-1 were repeated using2-methoxyphenethylamine(5 ml, 34.16 mmol) to afford 6.45 g of the titledcompound.

Preparation 1-4. 5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

The same procedures as in Preparation 1-1 were repeated using4,5-dimethoxyphenethylamine(5.0 g, 27.6 mmol) to afford 2.65 g of thetitled compound.

Preparation 1-5. 1-methoxymethyl-1,2,3,4-tetrahydroisoquinoline

Step 1: Preparation of methoxyacetic acid

A mixture solution of methoxyacetonitrile(10 g, 0.14 mole) and conc.hydrochloric acid was stirred for 30 minutes, then refluxed for another30 minutes, cooled to room temperature, diluted with water, extractedwith diethyl ether. The ether solution was separated, dried overanhydrous sodium sulfate, concentrated under reduced pressure to afford8.3 g of titled compound.

Step 2: Preparation of N-phenylethylmethoxyacetamide

Phenethylamine(11.6 ml, 92.1 mmol) was added dropwise to a solution ofdicyclohexylcarbodiimide(19 g, 92.1 mmol), methoxyacetic acid(8.3 g,92.1 mmol) in dichloromethane(50 ml) at room temperature. After additionwas completed, the reaction mixture was stirred for 1 hour at roomtemperature and the resulting solid was filtered. The filtrate waswashed with aqueous hydrochloric acid solution, and the organic layerwas dried over anhydrous sodium sulfate, concentrated under reducedpressure to afford 8.15 g of the titled compound.

Step 3: Preparation of 1-methoxymethyl-1,2,3,4-tetrahydroisoquinoline

The same procedures as in Step 2 and 3 of Preparation 1-1 were repeatedusing N-phenylethylmethoxyacetamide(8.1 g, 41.9 mmol) to afford 2.6 g ofthe titled compound.

Preparation 2: 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine

Step 1: Ethyl 2-methyl-3-oxo-4-methoxybutyrate

Zinc(18.1 ml, 275 mmol), methoxyacetonitrile(13.7 ml, 185 mmol), benzene(180 ml) and a catalytic amount of mercuric chloride were heated toreflux. A solution of ethyl 2-bromopropionate(35.9 ml, 275 mmol) inbenzene(30 ml) was added dropwise, then reflux continued for further ahour, and cooled to a room temperature. 10% Aqueous sulfuric acidsolution (325 ml) was added, and the organic layer was separated. Theaqueous layer was further extracted with ethyl ether and the combinedorganic layers washed with water and aqueous sodium bicarbonatesolution, then dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give 29.3 g of the titled compound.

Step 2: 2-amino-4-hydroxy-6-methoxymethyl-5-methylpyrimidine

Ethyl 2-methyl-3-oxo4-methoxybutyrate(10.5 g, 60 mmol) was added slowlyto a suspension of sodium methoxide (6.5 g, 120 mmol) indimethylformamide(10 ml) while maintaining the reaction temperatureunder 20° C. A solution of guanidine(5.7 g, 60 mmol) in ethanol wasadded to a reaction mixture, which was then refluxed for 5 hours, cooledto a room temperature, and neutralized with conc. sulfuric acid. Theresulting solid was filtered and dried to give 2.7 g of the titledcompound.

Step 3: 2,4-dihydroxy-6-methoxymethyl-5-methylpyrimidine

2-amino-4-hydroxy-6-methoxymethyl-5-methylpyrimidine (2.7 g, 16 mmol)was added to 20% aqueous hydrochloric acid solution (7 ml), and heatedto 70° C. A solution of sodium nitrite (2.3 g, 33.3 mmol) in water wasadded dropwise to a reaction mixture while maintaining the reactiontemperature under 70° C. The reaction mixture was cooled to a roomtemperature. The resulting solid was filtered and dried to give 1.5 g ofthe titled compound.

Step 4: 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine

A mixture solution of 2,4-dihydroxy-6-methoxymethyl-5-methyl pyrimidine(1.5 g, 8.8 mmol), phosphorous oxychloride(7ml) and N,N-dimethylaniline(0.9 ml) was refluxed for 3 hours, cooled to a room temperature, andthen poured into ice water. The aqueous layer was extracted withdichloromethane. The resulting organic layer was dried, concentrated,and purified by a silica gel column chromatography to give 1.3 g of thetitled compound.

Preparation 3. 4-morpholineacetic acid hydrochloride

Step 1: ethyl 4-morpholineacetate

Morpholine(1.65 ml, 18.9 mmol) was added dropwise to a soultion of ethylbromoacetate(1 ml, 9.0 mmol) in benzene (9 ml). The reaction mixture wasstirred for 2 hours at a room temperature, diluted with ethyl ether, andwashed with saturated NaCl solution. The separated organic layer wasdried over anhydrous sodium sulfate and concentrated under a reducedpressure to give 1.11 g of the titled compound as an oil. (Yield 71.2%)

NMR(CDCl₃): 1.3(t, 3H), 2.6(t, 4H), 3.2(s, 2H), 3.8(t, 4H), 4.2(q, 2H).

Step 2: 4-Morpholineacetic acid hydrochloride

Ethyl 4-morpholinoacetate (1.1 g, 6.3 mmol) was added to 3M hydrochloricacid solution (35 ml), refluxed for 2 hours, stirred for 1 day at a roomtemperature, and then concentrated under a reduced pressure. Theresulting residue was dissolved in methanol and reconcentrated. Theresulting solid was suspended in ethylether, filtered and dried under areduced pressure to give 1.05 g of the titled compound. (Yield 91.7%)

NMR (DMSO-d6): 3.3(s, 4H), 3.9(s, 4H), 4.2(s, 2H).

Preparation 4. 4-benzylpiperazineacetic acid dihydrochloride

Step 1: ethyl 4-benzylpiperazineacetate

4-Benzylpiperazine(3.3 ml, 18.9 mmol) was added to a solution of ethylbromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), which was then stirredfor 2 hours at a room temperature, diluted with ethyl ether, and washedwith saturated NaCl solution. The separated organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure to give2.38 g of the titled compound. (Yield 100%).

NMR(CDCl₃): 1.3(t, 3H), 2.6(t, 8H), 3.2(s, 2H), 3.6(s, 2H), 4.2(q, 2H),7.3(m, 5H).

Step 2: 4-benzylpiperazineacetic acid dihydrochloride

Ethyl 4-benzylpiperazineacetate (2.38 g, 9.0 mmol) was added to 3Mhydrochloric acid solution(12 ml), refluxed for 2 hours, stirred for 1day at a room temperature, and then concentrated under reduced pressure.The resulting residue was dissolved in methanol and reconcentrated. Theresulting solid was suspended in ethyl ether, filtered and dried under areduced pressure to give 2.14 g of the titled compound. (Yield 77.4%)

NMR(D2O): 3.3(s, 8H), 3.7(s, 2H), 4.0(s, 2H), 7.1(s, 5H).

Preparation 5. 1-piperidineacetic acid hydrochloride

Step 1:ethyl 1-piperidineacetate

Piperidine(1.87 ml, 18.9 mmol) was added dropwise to a solution of ethylbromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), stirred for 2 hours at aroom temperature, diluted with ethyl ether, washed with saturated NaClsolution. The separated organic layer was dried over anhydrous sodiumsulfate and concentrated under a reduced pressure to give 1.26 g of thetitled compound. (Yield 81.8%)

NMR(CDCl₃): 1.3(t, 3H), 1.5(m, 2H), 1.7(m, 4H), 2.5(t, 4H), 3.2(s, 2H),4.2(q, 2H).

Step 2: 1-piperidineacetic acid hydrochloride

Ethyl 1-piperidineacetate (1.26 g, 7.4 mmol) was added to 3Mhydrochloric acid solution (12 ml), which was then refluxed for 2 hours,stirred for 1 day at a room temperature, then concentrated under areduced pressure. The resulting residue was dissolved in methanol andreconcentrated. The resulting solid was suspended in ethyl ether,filtered and dried under a reduced pressure to give 0.87 g of the titledcompound. (Yield 65.3%). NMR(D2O): 1.0(m, 2H), 1.4(m, 4H), 2.5(m, 2H),3.1(m, 2H), 3.5(s, 2H).

EXAMPLE 15,6-dimethyl-2-(propylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Propylamine(0.44 g, 5.4 mmol) and triethylamine(0.38 ml, 2.7 mmol) wereadded to a mixture solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.8 mmol) in dimethylformamide(10 ml). The reaction mixture wasstirred for 5 hours at 130° C., cooled to a room temperature, dilutedwith dichloromethane, and then washed with aqueous sodium hydroxide andwater. The separated organic layer was dried over anhydrous magnesiumsulfate, concentrated under a reduced pressure, and then purified bycolumn chromatography to give free base form of the titled compound.Ethyl ether saturated with hydrochloric acid was added to a mixturesolution of the free base form of the titled compound in ethyl ether.The resulting solid was filtered and dried to obtain 490 mg of thetitled compound.

Yield: 81.8%; M.P.: 157-160° C.; ¹H-NMR(CDCl3): δ 1.0(t, 3H), 1.7(m,2H), 2.1(s, 3H), 2.4(s, 3H), 3.1(t, 2H), 3.4(q, 2H), 3.9(t, 2H), 4.8(s,2H), 7.2(m, 4H), 7.9(s, 1H), 13.8(s, 1H).

EXAMPLE 25,6-dimethyl-2-(3-allylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After allylamine(0.20 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol)were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.8 mmol) in dimethylformamide, 170 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield: 28.5%; M.P.: 192-194° C.; ¹H-NMR(CDCl3): δ 2.2(s, 3H), 2.4(s,3H), 3.1(t, 2H), 3.9(t, 2H), 4.1(t, 2H), 4.8(s, 2H), 5.3(q, 2H), 5.9(m,1H), 7.2(m, 4H), 8.0(s, 1H), 14.0(s, 1H).

EXAMPLE 35,6-dimethyl-2-butylamino4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After butylamine(0.53 ml, 5.4 mmol) and triethylamine(0.38 ml, 2.7 mmol)were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 300 mg of the titledcompound was obtained in accordance with the same procedure as inExample 1.

Yield: 48.0%; M.P.: 110-113° C.; ¹H-NMR(CDCl3): δ 1.0(t, 3H), 1.4(m,2H), 1.6(m, 2H), 2.1(s, 3H), 2.4(s, 3H), 3.1(t, 2H), 3.5(q, 2H), 3.9(t,2H), 4.8(s, 2H), 7.2(m, 4H), 7.9(s, 1H), 13.8(s, 1H).

EXAMPLE 45,6-dimethyl-2-isobutylamino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After isobutylamine(0.27 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 180 mg of the titledcompound was obtained in accordance with the same procedure as inExample 1.

Yield: 28.8%; M.P.: 169-172° C.; ¹H-NMR(CDCl3): δ 1.0(d, 6H), 1.9(m,1H), 2.1(s, 3H), 2.4(s, 3H), 3.1(t, 2H), 3.3(d, 2H), 3.9(t, 2H), 4.8(s,2H), 7.2(m, 4H), 8.0(s, 1H), 13.9(s, 1H).

EXAMPLE 55,6-dimethyl-2-(2-methoxyethylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After methoxyethylamine(0.23 ml, 2.7 mmol) and triethylamine(0.38 ml,2.7 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 470 mg of the titled compoundwas obtained in accordance with the same procedure as in Example 1.

Yield: 74.8%; M.P.: 145-150° C.; ¹H-NMR(CDCl3): δ 2.1(s, 3H), 2.4(s,3H), 3.1(t, 2H), 3.4(s, 3H), 3.6(m, 4H), 3.9(t, 2H), 4.8(s, 2H), 7.2(m,4H), 7.9(s, 1H), 14.0(s, 1H).

EXAMPLE 65,6-dimethyl-2-phenylethylamino4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After phenethylamine(0.34 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 600 mg of the titledcompound was obtained in accordance with the same procedure as inExample 1.

Yield: 84.4%; M.P.: 150-154° C.; ¹H-NMR(CDCl3): δ 2.1(s, 3H), 2.4(s,3H), 2.9(t, 2H), 3.1(t, 2H), 3.7(q, 2H), 3.9(t, 2H), 4.8(s, 2H), 7.2(m,9H), 8.1(s, 1H).

EXAMPLE 75,6-dimethyl-2-(1-naphthylmethyl)amino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 1-naphthylmethylamine(0.40 ml, 2.7 mmol) and triethylamine (0.38ml, 2.7 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.8 mmol) in dimethylformamide, 680 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield 87.7%; M.P.: 194-197° C.; ¹H-NMR(CDCl3): δ 2.1(s, 3H), 2.4(s, 3H),2.9(t, 2H), 3.8(t, 2H), 4.6(s, 2H), 5.1 (d, 2H), 7.0(m, 1H), 7.2(m, 3H),7.5(m, 4H), 7.8(d, 1H), 7.9(d, 1H), 8.2(d, 1H), 8.5(s, 1H), 14.1(s, 1H).

EXAMPLE 85,6-dimethyl-2-(cyclohexylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After cyclohexylamine(0.31 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 340 mg of the titledcompound was obtained in accordance with the same procedure as inExample 1.

Yield: 70.0%; M.P.: 173-177° C.; ¹H-NMR(CDCl3): δ 1.4(m, 6H), 1.8(m,2H), 1.9(m, 2H), 2.2(s, 3H), 2.4(s, 3H), 3.1(t, 2H), 3.9(t, 3H), 4.8(s,2H), 7.2(m, 4H), 7.9(d, 1H), 13.7(s, 1H).

EXAMPLE 95,6-dimethyl-2-(cyclopentylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After cyclopentylamine(0.27 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 270 mg of the titledcompound was obtained in accordance with the same procedure as inExample 1.

Yield: 41.8%; M.P.: 148-153° C.; ¹H-NMR(CDCl3): δ 1.6(m, 4H), 1.8(m,2H), 2.0(m, 2H), 2.1(s, 3H), 2.4(s, 3H), 3.1(t, 2H), 3.9(t, 2H), 4.2(q,1H), 4.8(s, 2H), 7.2(m, 4H), 8.0(d, 1H), 13.7(s, 1H).

EXAMPLE 105,6-dimethyl-2-(piperidin-1-yl)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After piperidine(0.27 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol)were added to a solution of2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 260 mg of the titledcompound was obtained in accordance with the same procedure as inExample 1.

Yield: 40.2%; M.P.: 77-82° C.; ¹H-NMR(CDCl3): δ 1.7(s, 6H), 2.2(s, 3H),2.7(s, 3H), 3.1(t, 2H), 3.9(t, 2H), 4.1(s, 4H), 4.8(s, 2H), 7.2(m, 4H),12.9(bs, 1H).

EXAMPLE 115,6-dimethyl-2-propylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After propylamine(0.43 ml, 5.22 mmol) and triethylamine(0.36 ml, 2.59mmol) were added to a solution of5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 530 mg of the titled compoundwas obtained in accordance with the same procedure as in Example 1.

Yield: 63.0%; M.P.: 162-164° C.; ¹H-NMR(CDCl3): δ 1.0(t, 3H), 1.7(q,5H), 2.2(s, 3H), 2.4(s, 311), 2.9(m, 1H), 3.1-3.7(m, 5H), 4.3(m, 1H),5.4(q, 1H), 7.2(m, 4H), 7.9(s, 1H), 13.8(s, 1H).

EXAMPLE 125,6-dimethyl-2-(3-allylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After allylamine(0.40 ml, 5.22 mmol) and triethylamine(0.36 ml, 2.59mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 510 mg of the titledcompound was obtained in accordance with the same procedure as inExample 1.

Yield: 85.0%; M.P.: 192-194° C.; ¹H-NMR(CDCl3): δ 1.7(d, 3H), 2.2(s,3H), 2.4(s, 3H), 4.6(s, 2H), 4.3(m, 1H), 5.1-5.5(m, 3H), 4.8(s, 2H),5.9(m, 1H), 7.2(m, 4H), 8.0(s, 1H), 13.9(s, 1H).

EXAMPLE 135,6-dimethyl-2-butylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After butylamine(0.52 ml, 5.22 mmol) and triethylamine(0.36 ml, 2.59mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.74 mmol) in dimethylformamide, 430 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield: 68.5%; M.P.: 105-107° C.; ¹H-NMR(CDCl3): δ 1.0(t, 3H), 1.4-1.7(m,4H), 1.7(d, 3H), 2.1(s, 3H), 2.4(s, 3H), 2.9(m, 1H), 3.2-3.7(m, 4H),4.3(m, 1H), 5.4(q, qH), 7.3(m, 4H), 7.8(s, 1H), 13.8(s, 1H).

EXAMPLE 145,6-dimethyl-2-isobutylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

After isobutylamine(0.26 ml, 2.58 mmol) and triethylamine(0.36 ml, 2.59mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.74 mmol) in dimethylformamide, 133 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield 2 0.0%; M.P.: 93-95° C.; ¹H-NMR(CDCl3): δ 0.9(d, 6H), 1.5(d, 3H),1.9(m, 1H), 2.1(s, 3H), 2.3(s, 3H), 2.8(m, 1H), 3.1(t, 2H), 3.2(m, 1H),3.5(m, 2H), 4.0(m, 1H), 5.1(q, 1H), 7.2(m, 4H).

EXAMPLE 155,6-dimethyl-2-(2-methoxyethylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hiydrochloride

After 2-methoxyethylamine(0.23 ml, 2.7 mmol) and triethylamine(0.38 ml,2.7 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 320 mg of the titled compoundwas obtained in accordance with the same procedure as in Example 1.

Yield: 50.7%; M.P.: 64-67° C.; ¹H-NMR(CDCl3): δ 1.6(d, 3H), 2.1(s, 3H),2.4(s, 3H), 2.9(m, 1H), 3.3(m, 1H), 3.4(s, 3H), 3.6(m, 5H), 4.3(m, 1H),5.4(q, 1H), 7.2(m, 4H), 7.8(s, 1H), 13.8(s, 1H).

EXAMPLE 165,6-dimethyl-2-phenylethylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 2-phenethylamine(0.33 ml, 2.61 mmol) and triethylamine(0.36 ml,2.59 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.74 mmol) in dimethylformamide, 500 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield: 70.2%; M.P.: 124-127° C.; ¹H-NMR(CDCl3): δ 1.7(d, 3H), 2.1(s,3H), 2.4(s, 3H), 3.0(m, 3H), 3.3(m, 1H), 3.7(m, 3H), 4.3(m, 1H), 5.4(q,1H), 7.2(m, 9H), 8.0(s, 1H), 13.8(s 1H).

EXAMPLE 175,6-dimethyl-2-(1-naphthylmethyl)amino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride

After 1-naphthylmethylamine(0.38 ml, 2.61 mmol) and triethylamine (0.36ml, 2.59 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.74 mmol) in dimethylformamide, 630 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield: 81.4%; M.P.: 179-182° C.; ¹H-NMR(CDCl3): δ 1.4(d, 3H), 2.1(s,3H), 2.4(s, 3H), 2.7(m, 1H), 3.0(m, 1H), 3.4(m, 1H), 4.1(m, 1H), 5.1(m,3H), 6.8(d, 1H), 7.1(m, 3H), 7.5(m, 4H), 7.8(d, 1H), 7.9(d, 1H), 8.1(d,1H), 8.5(s, 1H), 14.0(s, 1H).

EXAMPLE 185,6-dimethyl-2-(3-trifluoromethylphenylmethyl)amino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 3-trifluoromethylbenzylamine(0.30 ml, 2.61 mmol) andtriethylamine(0.36 ml, 2.59 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.74 mmol) in dimethylformamide, 630 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield: 78.2%; M.P.: 190-192° C.; ¹H-NMR(CDCl3): δ 1.5(d, 3H), 2.1(s,3H), 2.4(s, 3H), 2.8(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 4.2(m, 1H), 4.6(d,2H), 5.2(q, 1H), 7.1(m, 4H), 7.6(m, 4H), 8.6(s, 1H), 14.0(s, 1H).

EXAMPLE 195,6dimethyl-2-(cyclopentylamino)-4-(1-methyl-1,2,3,4tetrahydroisoquinolin-2-yl)pyrirnidinehydrochloride

After cyclopentylamine(0.26 ml, 2.61 mmol) and triethylamine(0.36 ml,2.59 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 550 mg of the titled compoundwas obtained in accordance with the same procedure as in Example 1.

Yield 84.8%; M.P.: 150-153° C.; ¹H-NMR(CDCl3): δ 1.6(d, 6H), 1.7-2.0(m,5H), 2.1(s, 3H), 2.4(s, 3H), 2.9(m, 1H), 3.1(m, 1H), 3.2(m, 1H), 3.6(m,1H), 4.2(m, 2H), 5.4(q, 1H), 7.2(m, 4H), 8.0(d, 1H), 13.6(s, 1H).

EXAMPLE 205,6-dimethyl-2-(cyclohexylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After cyclohexylamine(0.30 ml, 2.61 mmol) and triethylamine(0.36 ml,2.59 mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.74 mmol) in dimethylformamide, 550 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield 81.7%; M.P.: 140-144° C.; ¹H-NMR(CDCl3): δ 1.4(m, 5H), 1.6(d, 3H),2.0(m, 5H), 2.2(s, 3H), 2.4(s, 3H), 2.9(m, 1H), 3.2(m, 1H), 3.6(m, 1H),3.9(bs, 1H), 4.3(m, 1H), 5.4(q, 1H), 7.2(m, 4H), 7.8(d, 1H), 13.6(s,1H).

EXAMPLE 215,6-dimethyl-2-(piperidin-1-yl)-4-(1methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After piperidine(0.26 ml, 2.61 mmol) and triethylamine(0.36 ml, 2.59mmol) were added to a solution of2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5g, 1.74 mmol) in dimethylformamide, 490 mg of the titled compound wasobtained in accordance with the same procedure as in Example 1.

Yield 75.5%; M.P.: 103-107° C.; ¹H-NMR(CDCl3): δ 1.6(d, 3H), 1.7(s, 6H),2.1(s, 3H), 2.7(s, 3H), 2.9(m, 1H), 3.2(m, 1H), 3.5(m, 1H), 4.0(s, 4H),4.3(m, 1H), 5.4(q, 1H), 7.2(m, 4H), 13.2(s, 1H).

EXAMPLE 225,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1: 2-guanyl-4-methylthiazole hydrochloride

After refluxing a solution of 2-aminothiourea(11.08 g, 93.77 mmol) inethanol(85 ml), chloroacetone(8.2 ml, 103.15 mmol) was added dropwise tothe solution. The reaction mixture was stirred for 4 hours, and thenstand for 1 day, while maintaining the temperature under 10° C. Theresulting solid was filtered, washed with ethyl ether, and then driedunder a reduced pressure to give 11.7 g of the titled compound. (Yield:64.7%)

Step 2: 5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-hydroxypyrimidine

A mixture solution of ethyl 2- methylacetoacetate(0.7 ml, 5.19 mmol),sodium methoxide (0.56 g, 10.38 mmol), 2-guanyl4-methylthiazole (1.0 g,5.19 mmol), and methanol(13 ml) was refluxed and then stirred for 3hours. The reaction mixture was cooled to a room temperature and thenadjusted to pH 7 with hydrochloric acid. The resulting solid wagfiltered, washed with water and methanol, and then dried under a reducedpressure to give 0.98 g of the titled compound. (Yield: 32%)

Step 3: 5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-chloropyrimidine

The mixture solution of5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-hydroxypyrimidine (1.15 g,4-78 mmol), phosphorus oxychioride(7 ml), and dimethylformamide(5 ml)was heated to 70° C. for 30 minutes, cooled to a room temperature andthen poured into ice water. The aqueous layer was extracted withdichloromethane, washed with 1N sodium hydroxide solution, and thenwashed with water. The separated organic layer was concentrated and theresidual oil was suspended in a mixture solution of ethyl ether andhexane. The resulting solid was filtered and dried to give 0.42 g of thetitled compound. (Yield: 33.9%)

Step 4:5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

A soultion of5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-chloropyrimidine (0.41 g,1.6 mmol) 1-methyl-1,2,3,4-tetrahydioiasoquinoline(0.47 ml, 3.2 mmol)and dimethylformamide(2ml) was he a ted to 120° C. for 6 hours. dilutedwith dichiloromethane, and then washed with water. The separated organiclayer was dried over anhydrous magnesium sulfate and concentrated. Theresulting residue was purified by slica gel column chromatography, usinga solution of ethylacetate and hexane (1:2) as a eluent. Afterevaporating of the solvent, the residual oil was dissolved in a solutionof ethyl ether and ethyl acetate and treated with ethylether saturatedwith hydrochloric acid. The resulting solid was filtered and dried togive 0.5 g of the titled compound.

Yield :78%; M.P.: 183-185° C.; ¹H-NMR(DMSO-d6): δ 1.6(d, 3H), 2.2(s,3H), 2.3(s, 3H), 2.4(s, 3H), 2.9(m, 1H), 3.2(m, 1H), 3.7(m, 1H), 4.4(m,1H), 5.6(m, 1H), 6.7(s, 1H), 7.2(m, 4H), 7.4(m, 1H), 8.0(bs, 1H),12.8(bs, 1H).

EXAMPLE 235,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

The same procedures as in Step 4 of Example 22 were repeated using5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-chloropyrimidine(0.85 g,3.34 mmol), 1,2,3,4-tetrahydroisoquinoline(0.42 ml, 3.34 mmol) anddimethylformamide (5 ml) to afford 140 mg of the titled compound.

Yield: 10.8%; M.P.: 257-262° C.; ¹H-NMR(DMSO-d6): δ 2.2(s, 3H), 2.3(s,3H), 2.4(s, 3H), 3.1(s, 2H), 4.0(s, 2H), 6.7(s, 1H), 5.6(m, 1H), 7.2(d,4H).

EXAMPLE 245,6-dimethyl-2-(4-phenylthiazol-2-yl)amino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1: 2-guanyl-4-phenylthiazole hydrobromide

The same procedures as in Step 1 of Example 22 were repeated using2-aminothiourea(20 g, 169.26 mmol), 2-bromoacetophenone(35.38 g, 1.05eq.) and ethanol (170 mol) to afford 49.9 g of the titled compound.(Yield: 98.5%)

Step 2: 5,6-dimethyl-2-(4-phenylthiazol-2-yl)amino-4-hydroxypyrimidine

The same procedures as in Step 2 of Example 22 were repeated using2-guanyl-4-phenylthiazole hydrobromide(30.5 g, 101.94 mmol) and ethyl2-nmethylacetoaetate(14.4 ml, 101.94 mmol) to afford 5.6 g of the titledcompound. (Yield: 18.4%)

Step 3: 5,6-dimethyl-2-(4-phenylthiazol-2-yl)amino-4-chloropyrimidine

The same procedures as in Step 3 of Example 22 were repeated using5,6-dimethyl-2-(4-phenylthiazol-2-yl)amino-4-hydroxypyrimidine (5.6 g,18.77 mmol) and phosphorus oxychloride(7 ml) to afford 3.0 g of thetitled compound. (Yield: 50%)

Step 4:5,6-dimethyl-2-(4-phenylthiazol-2-yl)amino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

A mixture solution of5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-chloropyrimidine (0.36 g,1.14 mmol), 1,2,3,4-tetrahydroisoquinoline(0.16 ml, 1.25 mmol),triethylamine(0.16 ml, 1.25 mmol) and propyleneglycol(1.1 ml) was heatedto 140° C., stirred for 5 hours, diluted with dichloromethane, and thenwashed with water. The separated organic layer was dried over anhydrousmagnesium sulfate and concentrated. The resulting residue was purifiedby a silica gel column chromatography using, a soluton of ethyl acetateand hexane (1:3) as a eluent. After evaporating of the solvent, theresidual oil was dissolved in a solution of ethyl ether and ethylacetate and treated with ethylether saturated with hydrochloric acid.The resulting solid was filtered and dried to give 0.18 g of the titledcompound.

Yield: 35%; M.P.: 283-285° C.; ¹H-NMR(DMSO-d6): δ 2.2(s, 3H), 2.4(s,3H), 3.1(t, 2H), 3.7(t, 2H), 4.7(s, 2H), 7.0(s, 1H), 7.3(m, 7H), 7.9(d,2H).

EXAMPLE 256-methoxymethyl-5-methyl-2-(2-methylethylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1:6-methoxymethyl-5-methyl-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

1,2,3,4-tetrahydroisoquinoline(0.9 ml, 6.9 mmol) was added dropwise to asolution of 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3mmol) and triethylamine(0.96 ml, 6.9 mmol) in dimethylformamide andstirred for 5 hours at a room temperature. The reaction mixture wasdiluted with dichloromethane and washed with water and aqueous sodiumhydroxide solution. The organic layer was dried over anhydrous sodiumsulfate and concentrated under a reduced pressure. The resulting residuewas purified by a silica gel column chromatography to give 1.8 g of thetitled compound. (Yield: 94.0%)

Step 2:6-methoxymethyl-5-methyl-2-(2-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride

o-Toluidine(0.48 ml, 4.5 mmol) and triethylamine were added to asolution of6-methoxymethyl-5-methyl-2-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.9 g, 3 mmol) in dimethylformamide(5 ml) and stirred for 5 hours at130° C. The reaction mixture was cooled to a room temperature, dilutedwith dichloromethane, and washed with aqueous sodium hydroxide andwater. The organic layer was dried over anhydrous magnesium sulfate,concentrated, and the residual oil was purified by columnchromatography. The purified compound was dissolved in ethyl ether.Ethyl ether saturated with hydrochloric acid was added to a mixturesolution. The resulting solid was filtered and dried to give 400 mg ofthe titled compound.

Yield: 32.5%; M.P.: 178-183° C.; ¹H-NMR(CDCl3): δ 2.2(s, 3H), 2.4(s,3H), 2.9(m, 2H), 3.6(s, 3H), 3.9(m, 2H), 4.5(s, 2H), 4.8(s, 2H),7.0-7.1(m, 7H), 7.6(m, 1H), 10.2(s, 1H) 14(s, 1H).

EXAMPLE 266-methoxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 4-fluoroaniline(0.43 ml, 4.5 mmol) and triethylamine(0.63 ml, 4.5mmol) were added to a solution of6-methoxymethyl-5-methyl-2-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.9 g, 3 mmol) in dimethylformamide (5 ml), 190 mg of the titledcompound was obtained in accordance with the same procedure as in Step 2of Example 25.

Yield: 15%; M.P.: 226-237° C.; ¹H-NMR(CDCl3): δ 2.2(s, 3H), 3.1(m, 2H),3.6(s, 3H), 3.9(m, 2H), 4.5(s, 2H), 4.8(s, 2H), 7.0-7.3(m, 6H), 7.6(m,2H), 11.2(s, 1H), 13.5(s, 1H).

EXAMPLE 276-methoxymethyl-5-methyl-2-(4-fluoro-2-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 2-methyl-4-fluoroaniline(0.51 g, 4.5 mmol) and triethylamine (0.63ml, 4.5 mmol) were added to a solution of6-methoxymethyl-5-methyl-2-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.9 g, 3 mmol) in dimethylformamide (5 ml), 750 mg of thetitled compound was obtained in accordance with the same procedure as inStep 2 of Example 25.

Yield : 60%; M.P.: 157-159° C.; ¹H-NMR(CDCl3): δ 2.2(s, 3H), 2.4(s, 3H),2.9(m, 2H), 3.6(s, 3H), 3.8(m, 2H), 4.5(s, 2H), 4.8(s, 2H), 6.8-7.3(m,6H), 7.5(m, 1H), 10.2(s, 1H), 14.0(s, 1H).

EXAMPLE 286-methoxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1:6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-1,2,3,4tetrahydroisoquinolin-2-yl)pyrimidine

The same procedures as in Step 1 of Example 25 were repeated using2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) and1-methyl-1,2,3,4-tetrahydroisoquinoline(1.02 g, 6.93 mmol) to afford 1.2g of the titled compound. (Yield: 60%)

Step 2:6-methoxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 4-fluoroaniline(0.43 ml, 4.5 mmol) and triethylamine(0.63 ml, 4.5mmol) were added to a solution of6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.96 g, 3 mmol) in dimethylformamide(5 ml), 600 mg of the titledcompound was obtained in accordance with the same procedure as in Step 2of Example 25.

Yield 47%; M.P.: 228-233° C.; ¹H-NMR(CDCl3): δ 1.6(d 3H), 2.2(s, 3H),2.9(d, 1H), 3.1(m, 1H), 3.5-3.7(s+m, 4H), 4.3(bd, 2H), 4.5(dd, 2H),5.4(q, 1H), 6.9-7.3(m, 6H), 7.6(m, 2H), 11.2(s, 1H), 13.3(bs, 1H).

EXAMPLE 296-methoxymethyl-5-methyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 2-methyl-4-fluoroaniline(0.62 ml, 4.5 mmol) and triethylamine(0.63 ml, 4.5 mmol) were added to a solution of6-methoxymethyl-5-methyl-2-chloro4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.96g, 3 mmol) in dimethylformamide(5 ml), 600 mg of the titled compound wasobtained in accordance with the same procedure as in Step 2 of Example25.

Yield: 47%; M.P.: 175-177° C.; ¹H-NMR(CDCl3): δ 1.5(d 3H), 2.2(s, 3H),2.4(s, 3H), 2.8(d, 1H), 3.1(m, 1H), 3.4-3.7(s+m, 4H), 4.3(m, 1H), 4.5(s,2H), 5.4(qq, 1H), 6.8-7.6(m, 7H), 10.0(ss, 1H), 13.9(ss, 1H).

EXAMPLE 306-methoxymethyl-5-methyl-2-(2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After o-toluidine(0.32 ml, 3.0 mmol) and triethylamine(0.63 ml, 4.5mmol) were added to a solution of6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.96g, 3 mmol) in dimethylformamide(5 ml), 250 mg of the titled compound wasobtained in accordance with the same procedure as in Step 2 of Example25.

Yield: 20%; M.P.: 247-250° C.; ¹H-NMR(CDCl3): δ 1.5(d 3H), 2.2(s, 3H),2.4(s, 3H), 2.8(d, 1H), 3.1(m, 1H), 3.5-3.7(s+m, 4H), 4.3(bd, 1H),4.5(s, 2H), 5.3(q, 1H), 7.0-7.3(m, 7H), 7.6(d, 1H), 10.2(s, 1H),13.9(bs, 1H).

EXAMPLE 316-methoxymethyl-5-methyl-2-phenylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After aniline (2.41 ml, 26.4 mmol) and triethylamine(3.68 ml, 26.4 mmol)were added to a solution of6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(7g, 22 mmol) in dimethylformamide (20 ml), 4.1 g of the titled compoundwas obtained in accordance with the same procedure as in Step 2 ofExample 25.

Yield: 45%; M.P.: 208-212° C.; ¹H-NMR(CDCl3): δ 1.6(d, 3H), 2.2(s, 3H),2.8(d, 1H), 3.1-3.3(m, 1H), 3.4-3.7(s+m, 4H), 4.35(bd, 1H), 4.50(dd,2H), 5.45(q, 1H), 6.80-7.50(m, 7H), 7.65(d, 2H), 11.10(s, 1H), 13.50(bs,1H).

EXAMPLE 326-hydroxymethyl-5-methyl-2-phenylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

A solution of6-methoxymethyl-5-methyl-2-phenylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(4.0g, 9.7 mmol) in dichloromethane (50 ml) was cooled under 0° C. Borontribromide (1M-dichloromethane solution, 38.8 ml, 38.8 mmol) was addeddropwise to the solution. The reaction mixture was stirred for 30minutes at 0° C. and poured into ice water. The separateddichloromethane layer was washed with aqueous sodium bicarbonatesolution, dried over anhydrous sodium sulfate, concentrated under areduced pressure. Ethyl ether was added to the resulting residue to givea solid, which was then dissolved in ethanol and treated with ethylether saturated with hydrochloric acid to give 2.3 g of the titledcompound.

Yield: 59.5%; M.P.: 193-198° C.; ¹H-NMR(DMSO-d6): δ 1.6(d 3H), 2.2(s,3H), 2.9(d, 1H), 3.1(m, 1H), 3.0-3.2(m, 1H), 4.3(bd, 1H), 4.6(q, 2H),5.5(q, 1H), 7.0-7.4(m, 5H), 7.4(t, 2H), 7.6(d, 2H).

EXAMPLE 336-hydroxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

The same procedures as in Example 32 were repeated using6-methoxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.25g, 0.58 mmol) and borone tribromide(1M-dichloromethane solution, 2.5 ml,2.5 mmol) to afford 0.1 g of the titled compound.

Yield: 29%; M.P.: 223-226° C.; ¹H-NMR(DMSO-d6): δ 1.6(d, 3H), 2.2(s,3H), 2.9(d, 1H), 3.0-3.2(m, 1H), 3.6-3.8(t, 1H), 4.3(bd, 1H), 4.7(q,2H), 5.5(q, 1H), 7.0-7.4(m, 6H), 7.5-7.7(m, 2H).

EXAMPLE 346-hydroxymethyl-5-methyl-2-(2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

The same procedures as in Example 32 were repeated using6-methoxymethyl-5-methyl-2-(2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(9.7g, 22.1 mmol) and borone tribromide(1M-dichloromethane solution, 88.4ml, 88.4 mmol) to afford 4.7 g of the titled compound.

Yield: 54.7%; M.P.: 225-227° C.; ¹H-NMR(DMSO-d6): δ 1.5(d, 3H), 2.1(s,3H), 2.3(s, 3H), 2.8(bd, 1H), 3.0(m, 1H), 3.5(m, 1H), 4.2(m, 1H), 4.6(q,2H), 5.3(q, 1H), 7.1(s, 5H), 7.3(d, 2H), 7.7(d, 1H), 10.0(s, 1H),12.3(s, 1H).

EXAMPLE 355,6dimethyl-2-(4-fluorophenylamino)-4-(6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1:5,6-dimethyl-2-chloro-4-(6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

After 1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline(1.3 g, 7.3 mmol)and triethylamine(1.0 ml, 7.3 mmol) were added to a suspension of5,6-dimethyl-2,4-dichloropyrimidine(1.2 g, 6.64 mmol) indimethylformamide, the reaction mixture was stirred for 3 hours at 85°C. The reaction mixture was cooled to a room temperature and dilutedwith ethyl acetate. The organic layer was washed with water and aqueoussodium hydroxide, dried over anhydrous magnesium sulfate, concentratedunder a reduced pressure, and then purified by a silica gel columnchromatography to give 1.7 g of the titled compound. (Yield: 78.5%)

Step

2: 5,6-dimethyl-2-(4-fluorophenylamino)-4-(6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride

After 4-fluoroaniline(0.72 ml, 7.5 mmol) and triethylamine(1.0 ml, 7.3mmol) were added to a solution of5,6-dimethyl-2-chloro4-(6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(1.6g, 5.0 mmol) in dimethylformamide(10 ml), 1.26 g of the titled compoundwas obtained in accordance with the same procedure as in Step 2 ofExample 25.

Yield: 2260%; M.P.: 190-192° C.; ¹H-NMR(DMSO-d6): δ 1.6(d, 3H), 2.2(s,3H), 2.4(s, 3H), 2.6(s, 3H), 2.9(bd, 1H), 3.1(m, 1H), 3.6(m, 1H),4.2(dd, 1H), 5.4(q, 1H), 7.2-7.3(m, 6H), 7.5-7.7(dd, 2H), 10.2(s, 1H),12.9(s, 1H).

EXAMPLE 365,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

The same procedures as in Example 32 were repeated using5,6dimethyl-2-(4-fluorophenylamino)-4-(6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride(1.2 g, 2.8 mmol) and borone tribromide (1M-dichloromethanesolution, 11.2 ml, 11.2 mmol) to afford 179 mg of the titled compound.

Yield: 15.4%; M.P.: 147-150° C.; ¹H-NMR(CDCl3): δ 1.5(d, 3H), 2.2(s,3H), 2.4(s, 3H), 2.8(m, 1H), 3.0(m,1H), 3.5(m, 1H), 4.2(m, 1H), 5.2(q,1H), 6.8(m, 5H), 7.4(m, 2H), 10.0(s 1H), 13.8(s, 1H).

EXAMPLE 37 5,6-dimethyl-2-(4-fluorophenylamino)-4-(7-methoxy-1-methyl-1,2,3,4-tetrahydroisoq uinolin-2-yl)pyrimidine hydrochloride

Step 1:5,6-dimethyl-2-chloro-4-(7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

After 1-methyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (0.9 g, 5.1mmol) and triethylamine(0.7 ml, 5.1 mmol) were added to a suspension of5,6-dimethyl-2,4-dichloropyrimidine (0.8 g, 4.64 mmol) indimethylformamide, 1.0 g of the titled compound was obtained inaccordance with the same procedure as in Step 1 of Example 35. (Yield:70.3%)

Step 2: 5,6-dimethyl-2-(4-fluorophenylamino)-4-(7-methoxy- 1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride

After 4-fluoroaniline(0.32 ml, 3.3 mmol) and triethylamine(0.46 ml, 3.3mmol) were added to a solution of5,6-dimethyl-2-chloro-4-(7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.7g, 2.2 mmol) in dimethylformamide(5 ml), 0.55 g of the titled compoundwas obtained in accordance with the same procedure as in Step 2 ofExample 25.

Yield: 58.6%; M.P.: 122-125° C.; ¹H-NMR(CDCl3): δ 1.6(d, 3H), 2.2(s,3H), 2.4(s, 3H), 2.8(m, 1H), 3.1(m,1H), 3.5(m, 1H), 3.8(s, 3H), 4.2(m,1H), 5.4(q, 1H), 6.6(s, 1H), 6.8(d, 1H), 7.0(m, 3H), 7.5(m, 2H), 10.2(s,1H), 14.0(s, 1H).

EXAMPLE 385,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

The same procedures as in Example 32 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride(0.55 g, 1.3 mmol) and borone tribromide(1M-dichloromethane solution, 5.2 ml, 5.2 mmol) to afford 166 mg of thetitled compound.

Yield: 30.8%; M.P.: 157-160° C.; ¹H-NMR(DMSO-d6): δ 1.6(d, 3H), 2.2(s,3H), 2.4(s, 3H), 2.8(m, 1H), 3.0(m,1H), 3.5(m, 1H), 4.2(m, 1H), 5.4(q,1H), 6.6(s, 1H), 6.7(d, 1H), 7.0(d, 1H), 7.1(t, 2H) 7.5(m, 2H), 9.0(s,1H), 10.2(s, 1H), 14.0(s, 1H).

EXAMPLE 395,6-dimethyl-2-(4-fluorophenylamino)-4-(5-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1:5,6-dimethyl-2-chloro4-(5-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

After 1-methyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline(0.9 g, 5.1 mmol)and triethylamine(0.7 ml, 5.1 mmol) were added to a suspension of5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.64 mmol) indimethylformamide, 1.0 g of the titled compound was obtained inaccordance with the same procedure as in Step 1 of Example 35. (Yield:70.3%)

Step 2:5,6-dimethyl-2-(4-fluorophenylarnino)-4-(5-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 4-fluoroaniline(0.32 ml, 3.3 mmol) and triethylamine(0.46 ml, 3.3mmol) were added to a solution of5,6-dimethyl-2-chloro-4-(5-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.7g, 2.2 mmol) in dimethylformamide (5 ml), 0.55 g of the titled compoundwas obtained in accordance with the same procedure as in Step 2 ofExample 25.

Yield: 58.6%; M.P.: 122-125° C.; ¹H-NMR(CDCl3): δ 1.6(d, 3H), 2.2(s,3H), 2.4(s, 3H), 2.8(m, 1H), 3.1(m,1H), 3.5(m, 1H), 3.8(s, 3H), 4.2(m,1H), 5.4(q, 1H), 6.6(s, 1H), 6.8(d, 1H), 7.0(m, 3H), 7.5(m, 2H), 10.2(s,11H), 14.0(s, 1H).

EXAMPLE 405,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-5-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride

The same procedures as in Example 32 were repeated using5,6-dimethyl-2-(4-fluorophenylarnino)-4-(5-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyriridinehydrochloride(0.55 g, l.3 mmol) and borone tribromide(1M-dichloromethane solution, 5.2 ml, 5.2 mmol) to afford 166 mg of thetitled compound.

Yield: 30.8%; M.P.: 157-160° C.; ¹H-NMR(DMSO-d6): δ 1.6(d, 3H), 2.2(s,3H), 2.4(s, 3H), 2.8(m, 1H), 3.0(m,1H), 3.5(m, 1H), 4.2(m, 1H), 5.4(q,1H), 6.6(s, 1H), 6.7(d, 1H), 7.0(d, 1H), 7.1(t, 2H), 7.5(m, 2H), 9.0(s,1H), 10.2(s, 1H), 14.0(s, 1H).

EXAMPLE 415,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1:5,6-dimethyl-2-chloro-4-(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

After 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(1.6 g, 4.98mmol) and triethylamine(0.7 ml, 4.98 mmol) were added to a suspension of5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.53 mmol) indimethylformamide, 1.1 g of the titled compound was obtained inaccordance with the same procedure as in Step 1 of Example 35. (Yield:76%)

Step 2:5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

4-fluoroaniline(0.46 ml, 4.70 mmol) and triethylamine(0.66 ml, 4.70mmol) were added to a solution of5,6-dimethyl-2-chloro-4-(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(1.0g, 3.13 mmol) in dimethyifomiamide(5 ml) and then stirred for 3 hours at120° C. The reaction mixture was cooled to a room temperature anddiluted with dichloromethane. Aqueous sodium hydroxide solution wasadded to the reaction mixture, which was then stirred. Thedichloromethane layer was dried over anhydrous magnesium sulfate,concentrated under a reduced pressure. The resulting residue waspurified by a silica gel column chromatography and dissolved in ethanol.Ethyl ether saturated with hydrochloric acid was added to the solution.The resulting solid was filtered and dried to give 530 mg of the titledcompound.

Yield: 39.3%; M.P.: 198-201° C.; ¹H-NMR(DMSO-d6): δ 1.1(d, 2H), 1.3(d,1H), 2.0(d, 3H), 2.4(s, 3H), 3.8(d, 1H), 4.0(m, 1H), 4.2(d, 2H), 5.2(q,1H), 7.3(t, 3H), 7.6(q, 3H), 10.5(s, 1H).

EXAMPLE 425,6-dimethyl-2-(4-fluorophenylamino)-4-(5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1:5,6-dimethyl-2-chloro-4-(5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

After 5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline(10 g, 4.82mmol) and triethylamine (0.67 ml, 4.82 mmol) were added to a suspensionof 5,6-dimethyl-2,4-dichloropyrimidine(0.71 g, 4.02 mmol) indimethylformamide, 1.02 g of the titled compound was obtained inaccordance with the same procedure as in Step 1 of Example 35. (Yield:72.8%)

Step 2:5,6-dimethyl-2-(4-fluorophenylamino)-4-(5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

After 4-fluoroaniline(0.40 ml, 4.13 mmol) and triethylamine(0.58 ml,4.13 mmol) were added to a solution of5,6-dimethyl-2-chloro-4-(5,8-dimethoxy-1-methyl-1,2,3,4tetrahydroisoquinolin-2-yl)pyrimidine(1.0 g, 2.87 mmol) in dimethylformamide(5 ml), 0.67 g of the titledcompound was obtained in accordance with the same procedure as in Step 2of Example 25. (Yield: 51.2%)

M.P.: 251-253° C.; NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H),2.8(m, 2H), 3.5(m, 2H), 3.8(d, 6H), 4.0(m, 1H), 5.2(q, 1H), 6.6(s, 2H),7.0(t, 2H), 7.5(q, 2H)

EXAMPLE 435,6-dimethyl-2-(4-fluorophenylamino)-4-(5,8-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

The same procedures as in Example 32 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride(0.6 g, 1.3 mmol) and borone tribromide(1M-dichloromethanesolution, 5.2 ml, 5.2 mmol) to afford 124 mg of the titled compound.

Yield 48.1%; M.P.: 275-278° C.; ¹H-NMR(DMSO-d6+TFA): δ 1.6(d, 3H),2.2(s, 3H), 2.4(s, 3H), 2.8(m, 2H), 3.6(m, 1H), 4.3(d, 1H), 5.6(s, 1H),6.6(s, 2H), 7.2(t, 2H), 7.7(q, 2H).

EXAMPLE 446-methoxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

Step 1:6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-6-methoxy-1,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine

After 1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline(1.2 g, 6.8 mmol)and triethylamine(0.96 ml, 6.9 mmol) were added to a suspension of2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) indimethylformamide, 2.0 g of the titled compound was obtained inaccordance with the same procedure as in Step 1 of Example 35. (Yield:73.6%)

Step 2:6-methoxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride

After 4-fluoroaniline(0.32 ml, 3.3 mmol) and triethylamine(0.46 ml, 3.3mmol) were added to a solution of6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(1.0 g, 2.3 mmol) in dimethylformamide(5 ml), 0.56 g of the titledcompound was obtained in accordance with the same procedure as in Step 2of Example 25.

Yield 53.4%; ¹H-NMR(CDCl3): 1.5(d, 3H), 2.2(s, 1H), 2.7(m, 1H), 3.1(m,1H), 3.5(s, 3H), 3.8(s, 3H), 4.0(m, 1H), 4.4(s, 2H), 5.1(q, 1H), 6.6(m,1H), 6.8(m, 1H), 6.9(m, 3H), 7.5(m, 2H).

EXAMPLE 456-hydroxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride

The same procedures as in Example 32 were repeated using6-methoxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl1-6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinehydrochloride(0.5 g, 1.1 mmol) and boron tribromide(1M-dichloromethanesolution, 4.4 ml, 4.42 mmol) to afford 210 mg of the titled compound.

Yield 44.5%; M.P.: 181-184° C.; ¹H-NMR(DMSO-d6): δ 1.5(d, 3H), 2.1(s,3H), 2.6(d, 1H), 2.8-3.1(m, 1H), 3.0(m,1H), 3.5(m, 1H), 3.9(m, 1H),4.4(d, 2H), 4.9-5.1(m, 2H), 6.6(m, 2H), 6.8-7.1(m, 3H), 7.6-7.9(m, 2H),9.2(s, 2H).

EXAMPLE 465-hydroxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)-pyrimidine

Step 1:6-methyl-4-hydroxy-2-(4-fluorophenylamino)pyrimidine

A mixture solution of ethyl acetoacetate(3.8 ml, 30.3 mmol),4-fluorophenylguanidine carbonate(5 g, 26.3 mmol), anddimethylformamide(5 ml) was refluxed for 2 hours and cooled to a roomtemperature. Ethyl ether was added to the reaction mixture and theresulting solid was filtered, washed with ethyl ether, and concentratedunder a reduced pressure to give 1.74 g of the titled compound. (Yield30%)

Step 2:6-methyl-4-chloro-2-(4-fluorophenylamino)pyrimidine

A reaction mixture of6-methyl-4-hydroxy-2-(4-fluorophenylamino)pyrimidine (1.74 g, 7.93 mmol)and phosphorus oxychloride was stirred for 1 hour at a room temperatureand then dissolved in dichloromethane. Water was added dropwise to thereaction mixture and stirred for 30 minutes. The separated organic layerwas washed with 2N NaOH solution, dried over anhydrous magnesiumsulfate, and then concentrated under a reduced pressure to give 1.57 gof the titled compound. (Yield 83.5%)

NMR (CDCl3): 2.4(s, 3H), 6.6(s, 1H), 7.0(m, 3H), 7.6(m, 2H).

Step 3:6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin)-2-(4-fluorophenylamino)pyrimidine

A reaction mixture of6-methyl-4-chloro-2-(4-fluorophenylamino)pyrimidine(1.4 g, 5.89 mmol),1-methyl-1,2,3,4-tetrahydroisoquinolin(1.12 g, 7.66 mmol),triethylamine(1.06 ml, 7.66 mmol), and propylene glycol(19 ml) wasstirred for 2 hours at 120° C., cooled to a room temperature, dilutedwith dichloromethane, and washed with water. The separated organic layerwas dried over anhydrous sodium sulfate, concentrated under a reducedpressure and the residual oil was purified by a silica gel columnchromatography (ethylacetate/n-hexane=1/1) to give 1.98 g of the titledcompound. (Yield 96.4%)

NMR (CDCl3): 1.5(d, 3H), 2.3(s, 3H), 2.9(m, 2H), 3.5(m, 1H), 4.2(m, 1H),5.4(br, 1H), 6.0(s, 1H), 6.8(s, 1H), 7.0(m, 2H), 7.2(m, 4H), 7.5(m, 2H).

Step 4:5-hydroxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)pyrimidine

A mixture solution of6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin)-2-(4-fluorophenylamino)pyrimidine(1.3g, 3.73 mmol), formaline(37%, 30 ml) and p-formaldehyde (20 g) wasstirred for 1 day at 80° C., extracted with dichloromethane, and thenwashed with aqueous 1N-NaOH solution and water. The separated organiclayer was concentrated under a reduced pressure and the residual oil waspurified by a silica gel column chromatography (ethylacetate/n-hexane=1/1) to give 0.17 g of the titled compound. (Yield 12%)

NMR (CDCl3): 1.6(d, 3H), 2.4(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.2(m, 1H), 4.6(q, 2H), 5.4(q, 1H), 6.9(m, 2H), 7.2(m, 4H), 7.5(m, 2H)

EXAMPLE 475,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methoxymethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine

Step 1:5,6-dimethyl-2-chloro-4-(1-methoxymethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine

After 1-methoxymethyl-1,2,3,4-tetrahydroisoquinolin(0.5 g, 2.82 mmol)and triethylamine(0.4 ml, 2.82 mmol) were added to a suspension of5,6-dimethyl-2,4-dichloropyrimnidine(0.48 g, 2.68 mmol) indimethylformamide (5 ml), 0.5 g of the titled compound was obtained inaccordance with the same procedure as in Step 1 of Example 35.

Step 2:5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methoxymethyl-1,2,3,4-tetra-hydroisoquinolin-2-yl)-pyrimidine

After 4-fluoroaniline(0.15 ml, 1.57 mmol) and triethylamine(0.21 ml,1.53 mmol) were added to a solution of5,6-dimethyl-2-chloro-4-(1-methoxy-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.57 mmol) in dimethylfomiamide (5 ml), 0.4 g of the titledcompound was obtained in accordance with the same procedure as in Step 2of Example 25(Yield: 63.7%).

M.P.: 193-195° C.; NMR (DMSO-d6): 2.2(s, 3H), 2.3(s, 3H), 2.8-3.2(m,2H), 3.4(s, 3H), 3.6-4.0(m, 3H), 4.3(bd, 1H), 5.5(bs, 1H), 7.0-7.5(m,6H), 7.5-7.8(m, 2H), 9.6(s, 1H)

EXAMPLE 485,6-dimethyl-2-(4-fluorophenylamino)-4-(1-hydroxymethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine

The same procedures as in Example 32 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methoxymethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine(0.4g, 1.0 mmol) and boron tribromide(1M-dichloromethane solution, 4.0 ml,4.0 mmol) to afford 150 mg of the titled compound.

Yield: 36%; M.P.: 198-200° C.; ¹H-NMR(DMSO-d6): δ 2.2(s, 3H), 2.4(s,3H), 2.8-3.2(m, 2H), 3.6-4.0(m, 3H), 4.3(bd, 1H), 5.5(bs, 1H),7.0-7.4(m, 6H), 7.4-7.7(m, 2H), 10.4(s, 1H).

EXAMPLE 495,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluoro-2-hydroxyphenylamino)pyrimidine

Step 1: 4-fluoro-2-methoxynitrobenzene

Potassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5mmol) in ethanol (100 ml), which was then refluxed for 12 hours. Theresulting solid was filtered, washed with ethanol, and concentrated. Theresulting oily residue was diluted with ethyl acetate and washed withwater. The separated organic layer was concentrated and the residual oilwas purified by column chromatography(ethylacetate/hexane=1/3) to give1.65 g of the titled compound. (Yield 9.7%).

NMR (CDCl₃): 4.0 (s, 3H), 6.8 (m, 2H), 8.0 (m, 1H).

Step 2: 4-fluoro-2-methoxy-aniline

Paladium/carbon(Pd/C, 5%, 0.5 g) was added to a solution of4-fluoro-2-methoxynitrobenzene (1.65 g, 9.6 mmol) in ethanol, which wasthen stirred for 1 hour under 30 psi of hydrogen pressure. The reactionmixture was filtered to remove paladium/carbon, and concentrated to give1.35 g of the titled compound. (Yield 100%)

NMR (CDCl₃): 3.8 (s, 3H), 6.5 (m, 3H).

Step 3:5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluoro-2-methoxyphenylamino)pyrimidine

A reaction mixture of 4-fluoro-2-methoxy-aniline(0.155 g, 1.10 mmol),5,6-dimethyl-2-chloro4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.24lg, 0.84 mmol), triethylamine(0.15 ml, 1.1 mmol) and propyleneglycol (2ml) was heated to 140° C. for 5 hours, cooled to a room temperature,diluted with dichloromethane(10 ml), and then washed with water. Theseparated organic layer was concentrated and the residual oil waspurified by column chromatography(ethylacetate/N-hexane=1/1) to give0.247 g of the titled compound. (Yield 75.2%)

NMR (CDCl₃): 1.5 (d, 3H), 2.2 (s, 3H), 2.4 (s, 3H), 2.8 (m, 1H), 3.2 (m,1H), 3.5 (m, 1H), 3.8 (s, 3H), 4.0 (m, 1H), 5.0 (q, 1H), 6.6 (m, 6H),7.0(d, 1H).

Step 4:5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluoro-2-hydroxyphenylamino)pyrimidine

Boron tribromide (1M dichloromethane solution, 1.9 ml, 1.9 mmol) wasadded dropwise to a solution of5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluoro-2-methoxyphenylamino)pyrimidine(0.247g, 0.63 mmol) in dichloromethane(2 ml) at 0° C., stirred for 1 hour, andpoured into ice water. The separated organic layer was concentrated andthe residual oil was purified by column chromatography(dichloromethane/methanol=10/1) to give 57 mg of the titled compound.(Yield 24%) NMR (CDCl₃): 1.5 (d, 3H), 2.2 (s, 3H), 2.3 (s, 3H), 2.7 (m,1H), 3.1 (m, 1H), 3.5 (m, 1H), 3.9 (m, 1H), 5.0 (q, 1H), 6.6 (m, 6H),7.0 (d, 1H).

EXAMPLE 505-methyl-6-acetoxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

Acetyl chloride (2.71 μl, 39.6 μmol) and triethylamine(20 μl, 142.6μmol) were added to a suspension of5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(10 mg, 26.4 μmol) in dichloromethane(1 ml) and stirred for 1 day at aroom temperature. The reaction mixture was purified with a silica gelcolumn chromatography (ethylacetate/n-hexane=1/1) to give 12 mg of thetitled compound.

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 6H), 2.8(m, 1H), 3.2(m, 1H), 4.0(m, 1H),5.0(s, 2H), 5.2(q, 1H), 6.9(m, 3H), 7.2(m, 4H), 7.5(m, 2H).

EXAMPLE 51-74

The same procedures as in Example 50 were repeated using5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(10mg, 26.4 μmol), correspondent acylchloride(39.6 μmol) andtriethylamine(20 μl, 142.6 μmol) to give the following titled compound.

EXAMPLE 515-methyl-6-ethylcarbonyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.2(t, 3H), 1.5(d, 3H), 2.2(s, 3H), 2.4(q, 2H), 2.8(m, 1H),3.2(m, 1H), 3.6(m, 1H), 4.0(m, 1H), 5.0(s, 2H), 5.1(q, 1H), 6.8(s, 1H),6.9(t, 2H), 7.2(m, 4H), 7.5(m, 2H).

EXAMPLE 525-methyl-6-isopropylcarbonyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.1(d, 6H), 1.6(d, 3H), 2.2(s, 3H), 2.7(m, 2H), 3.2(m, 1H),3.6(m, 1H), 4.0(m, 1H), 5.1(m, 2H), 7.0(m, 3H), 7.2(m, 4H), 7.5(m, 2H).

EXAMPLE 535-methyl-6-butylcarbonyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 0.9(t, 3H), 1.4(m, 3H), 1.6(m, 4H), 2.2(s, 3H), 2.4(t, 2H),2.8(m, 1H), 3.2(m, 2H), 3.6(m, 1H), 4.0(m, 1H), 5.1(m, 3H), 6.9(m, 3H),7.2(m, 4H), 7.5(m, 2H).

EXAMPLE 545-methyl-6-cyclopropylcarbonyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 0.9(m, 2H), 1.1(m, 2H), 1.5(d, 3H), 1.7(m, 1H), 2.2(s, 3H),2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H), 4.0(m, 1H), 5.0(s, 3H), 5.1(q, 1H),6.8(m, 1H), 6.9(t, 2H), 7.2(m, 4H), 7.5(m, 2H).

EXAMPLE 555-methyl-6-cyclobutylcarbonyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(m, 3H), 2.2(s, 3H), 2.3(m, 3H), 2.8(m, 1H),3.2(m, 2H), 3.5(m, 1H), 3.9(m, 1H), 5.0(s, 2H), 5.1(q, 1H), 6.8(s, 1H),6.9(m, 2H), 7.1(m, 4H), 7.5(m, 2H).

EXAMPLE 565-methyl-6-cyclohexylcarbonyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.3(m, 2H), 1.4(m, 2H), 1.5(d, 3H), 1.6(m, 2H), 1.9(m, 2H),2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H), 4.0(m, 1H), 5.0(m, 2H),5.1(q, 1H), 6.8(s, 1H), 6.9(m, 2H), 7.1(m, 4H), 7.5(m, 2H).

EXAMPLE 575-methyl-6-{(2-ethoxycarbonylethyl)carbonyloxymethyl}-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.2(t, 3H), 1.5(d, 3H), 2.2(s, 3H), 2.7(m, 5H), 3.2(m, 1H),3.5(m, 1H), 4.0(m, 1H), 4.2(q, 2H), 5.1(m, 3H), 7.0(m, 3H), 7.2(m, 4H),7.5(m, 2H)

EXAMPLE 585-methyl-6-benzoyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.5(m, 1H),4.0(m, 1H), 5.2(q, 1H), 5.3(s, 2H), 6.8(t, 2H), 7.1(m, 4H), 7.5(m, 6H),2H).

EXAMPLE 595-methyl-6-(4-methylbenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.5(s, 3H), 2.8(m, 1H), 3.2(m, 1H),3.6(m, 1H), 4.0(m, 1H), 5.2(q, 1H), 5.3(s, 2H), 6.8(t, 2H), 7.2(m, 5H),2H), 8.0(m, 3H).

EXAMPLE 605-methyl-6-(4-propylbenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.0(m, 3H), 1.6(d, 3H), 1.7(m, 2H), 2.2(s, 3H), 2.7(m, 2H),2.8(m, 1H), 3.2(m, 1H), 3.5(m, 1H), 4.0(m, 1H), 5.2(q, 1H), 5.3(s, 2H),6.8(t, 2H), 7.2(m, 6H), 7.5(m, 2H), 8.0(m, 3H).

EXAMPLE 615-methyl-6-(4-pentylbenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 0.9(m, 5H), 1.3(m, 4H), 1.6(d, 3H), 2.2(s, 3H), 2.6(m, 3H),3.2(m, 1H), 3.5(m, 1H), 4.0(m, 1H), 5.2(q, 1H), 5.3(s, 2H), 6.8(t, 2H),7.2(m, 6H), 7.5(m, 2H), 8.0(m, 3H).

EXAMPLE 625-methyl-6-(3-fluorobenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.2(q, 1H), 5.3(s, 2H), 6.8(t, 2H), 7.2(m, 6H), 7.5(m, 2H),7.9(m, 2H).

EXAMPLE 635-methyl-6-(3-trifluoromethylbenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.2(q, 1H), 5.4(s, 2H), 6.8(m, 3H), 7.2(m, 4H), 7.5(m, 2H),7.6(t, 1H), 7.8(d, 1H), 8.4(m, 2H).

EXAMPLE 645-methyl-6-(2,3-difluorobenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.1(q, 1H), 5.3(s, 2H), 6.8(s, 3H), 7.1(m, 5H), 7.4(m, 3H),7.8(m. 1H).

EXAMPLE 655-methyl-6-(2-chlorobenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl3): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.1(q, 1H), 5.3(s, 2H), 6.8(m, 3H), 7.2(m, 5H), 7.6(m, 4H),7.9(d, 1H)

EXAMPLE 665-methyl-6-(3-methoxyphenyl)acetoxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.8(m, 1H), 3.1(m, 1H), 3.6(m, 1H),3.7(s, 2H), 3.8(s, 3H), 3.9(m, 1H), 5.1(m, 3H), 6.8(m, 7H), 7.2(m, 4H)7.5(m, 2H).

EXAMPLE 675-methyl-6-(4-methoxyphenyl)acetoxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.5(m, 1H),3.6(s, 2H), 3.7(s, 3H), 3.9(m, 1H), 5.1(m, 3H), 5.3(s, 2H), 6.8(s, 1H),6.9(m, 4H), 7.2(m, 6H), 7.5(m, 2H).

EXAMPLE 685-methyl-6-(4-nitrobenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.1(q, 1H), 5.3(s, 2H), 6.9(m, 3H), 7.2(m, 4H), 7.5(m, 2H),8.3(s 4H).

EXAMPLE 695-methyl-6-(3-cyanobenzoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.1(q, 1H), 5.3(s, 2H), 6.8(m, 3H), 7.1(m, 4H), 7.4(m, 2H),7.6(t, 2H), 7.9(d, 1H), 8.4(m, 2H).

EXAMPLE 705-methyl-6-(1-naphthoyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.1(q, 1H), 5.4(s, 2H), 6.8(m, 3H), 7.1(m, 4H), 7.5(m, 5H),7.9(d, 1H), 8.0(d, 1H), 8.3(d, 1H), 9.0(d, 1H).

EXAMPLE 715-methyl-6-benzyloxyacetoxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.5(m, 1H),4.0(m, 1H), 4.2(s, 2H), 4.6(s, 2H), 5.1(m, 3H), 6.8(s, 1H), 7.0(t, 2H),4H), 7.4(m, 7H).

EXAMPLE 725-methyl-6-cinnamoyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.6(m, 1H),4.0(m, 1H), 5.2(m, 3H), 6.6(d, 1H), 6.9(m, 3H), 7.1(m, 4H). 7.5(m, 7H),7.8(d, 1H).

EXAMPLE 735-methyl-6-crotonyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 1.9(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 2H),3.5(m, 1H), 4.0(m, 1H), 5.1(m, 3H), 6.0(m, 1H), 6.9(m, 3H), 7.1(m, 4H),7.5(m, 2H).

EXAMPLE 745-methyl-6-(thiophen-2-yl-acetoxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.8(m, 1H), 3.1(m, 1H), 3.5(m, 1H),3.9(m, 3H), 5.1(m, 3H), 6.7(s, 1H), 7.0(m, 4H), 7.2(m, 5H), 7.5(m, 2H).

EXAMPLE 75-113

The same procedures as in Example 50 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(10 mg, 26.4 μmol), correspondentacylchloride(39.6 μmol) and triethylamine(20 μl, 142.6 μmol) to give thefollowing titled compound.

EXAMPLE 755,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-acetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.4(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 2H).

EXAMPLE 765,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-ethylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.2(t, 3H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.6(q, 2H),2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H),7.5(m, 2H).

EXAMPLE 775,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-isopropylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine.

NMR(CDCl₃): 1.3(d, 6H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.8(m, 2H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 2H).

EXAMPLE 785,6-dimethyl-2-(4-fluorophenylamnino)-4-(1-methyl-6-butylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 0.9(m, 3H), 1.5(m, 5H), 1.7(m, 2H), 2.1(s, 3H), 2.3(s, 3H),2.5(t, 2H), 2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H),7.0(m, 6H), 7.5(m, 2H).

EXAMPLE 795,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-cyclopropylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.0(m, 2H), 1.1(m, 2H), 1.5(d, 3H), 1.8(m, 1H), 2.1(s, 3H),2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H),6.9(m, 6H), 7.5(m, 2H).

EXAMPLE 805,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-cyclobutylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 20(m, 4H), 2.1(s, 3H), 2.3(s, 5H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 2H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 2H).

EXAMPLE 815,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-cyclohexylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.2(m, 9H), 1.5(d, 3H), 1.6(m, 1H), 2.1(s, 3H), 2.3(s, 3H),2.5(m, 1H), 2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H),6.9(m, 6H), 7.5(m, 2H).

EXAMPLE 825,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2-ethoxycarbonylethyl)carbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.3(t, 3H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 3H)2H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 4.1(q, 2H), 5.1(q, 1H), 7.0(m,5H), 7.1(m, 1H), 7.5(m, 2H).

EXAMPLE 835,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-benzoyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.6(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.8(m, 1H), 3.2(m, 1H),3.6(m, 1H), 4.0(m, 1H), 5.2(q, 1H), 7.0(m, 4H), 7.2(m, 1H), 7.5(m, 5H),8.0(s, 1H), 8.2(d, 2H).

EXAMPLE 845,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-methylbenzoyioxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.4(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 8H), 7.5(m, 2H),8.1(d, 2H).

EXAMPLE 855,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-ethylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.3(t, 3H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 3H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 7H), 7.3(m, 1H),7.5(m, 2H), 8.1(d, 2H).

EXAMPLE 865,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-propylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.0(t, 3H), 1.5(d, 3H), 1.8(m, 2H), 2.1(s, 3H), 2.3(s, 3H),2.7(m, 3H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H),7.3 (m, 1H), 7.5(m, 3H), 8.1(d, 2H).

EXAMPLE 875,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-t-butylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.3(s, 9H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 4H),8.1(m, 2H).

EXAMPLE 885,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-pentylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 0.9(m, 5H), 1.3(m, 4H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H),2.7(m, 3H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H),7.3(m, 2H), 7.5(m, 2H), 8.1(m, 2H).

EXAMPLE 895,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2-chlorobenzoyloxy)-1,2,3,4-ttrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 5H), 8.1(d, 1H).

EXAMPLE 905,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-chlorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrinmidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 5H), 7.1(m, 1H), 7.5(m, 4H),8.1(d, 2H).

EXAMPLE 915,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(3-chlorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 3.1(m, 1H), 3.5(m, 1H),3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 4H), 8.1(m, 2H).

EXAMPLE 925,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2,4-dichloro-5-fluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 2H), 7.6(d, 2H),7.8(d, 2H).

EXAMPLE 935,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2,4,6-trichlorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 7H), 7.5(m, 3H).

EXAMPLE 945,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(3-fluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 5H), 7.2(m, 1H), 7.3(m, 1H),7.5(m, 3H), 8.0(m, 2H).

EXAMPLE 955,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2,3-difluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine.

NMR (CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 7H), 7.6(m, 3H), 7.9(m, 1H).

EXAMPLE 965,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2,6-difluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 8H), 7.5(m, 3H).

EXAMPLE 975,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-(2,4-difluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 8H), 7.5(m, 2H), 8.1(m, 1H).

EXAMPLE 985,6-dimethyl-2-(4-fluorophenylamino)-{1-methyl-6(2,3,4-trifluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 7H), 7.5(m, 2H), 7.9(m, 1H).

EXAMPLE 995,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2,3,6-trifluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 7H), 7.5(m, 3H).

EXAMPLE 1005,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(2,4,5-trifluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl)}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 7H), 7.5(m, 2H), 8.0(m, 1H).

EXAMPLE 1015,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(3-trifluoromethylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 2H), 7.6(m, 1H),7.9(m, 1H), 8.4(m, 2H).

EXAMPLE 1025,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-(4-trifluoromethylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.3(m, 2H), 7.5(m, 2H),8.2(m, 2H).

EXAMPLE 1035,6-dimethyl-2-(4-fluorophenylamino)-4-{1-metiyl-6-(2,3,4,5-tetrafluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 2H), 7.7(m, 1H).

EXAMPLE 1045,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(3-methoxyphenyl)acetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 6H), 5.1(q, 1H), 7.0(m, 9H), 7.3(m, 1H), 7.5(m, 2H).

EXAMPLE 1055,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-methoxyphenyl)acetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine.

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 6H), 5.1(q, 1H), 7.0(m, 9H), 7.3(m, 1H), 7.5(m, 2H).

EXAMPLE 1065,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-butoxybenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.0(m, 3H), 1.2(m, 2H), 1.5(d, 3H), 1.7(m, 2H), 2.1(s, 3H),2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 4.1(t, 2H),1H), 7.0(m, 8H), 7.5(m, 2H), 8.1(m, 2H).

EXAMPLE 1075,6-diinethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-nitrobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 2H), 8.4(m, 4H).

EXAMPLE 1085,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(3-cyanobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrinidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 2H), 7.6(d, 1H),7.9(d, 1H), 8.4(m, 2H).

EXAMPLE 1095,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(1-naphthoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 5H), 7.9(d, 1H),8.1(d, 1H), 8.5(d, 1H), 9.0(d, 1H).

EXAMPLE 1105,6dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-cinnamoyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.6(d, 1H), 6.9(m, 6H), 7.5(m, 6H),7.8(d, 1H).

EXAMPLE 1115,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-crotonyloxy-1,2,3,4-tetrahydroissoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.0(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.0(d, 1H), 6.9(m, 5H),7.2(m, 2H), 7.5(m, 2H).

EXAMPLE 1125,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(thiophen-2-yl-acetoxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 4.1(s, 2H), 5.1(q, 1H), 6.9(m, 9H), 7.5(m, 2H).

EXAMPLE 1135,6-dimethy-2-(4-fluorophenylamino)-4-(1-methyl-6-benzyloxyacetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 2H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, IH), 3.1(m, 1H),3.5(m, 1H), 4.0(m, 1H), 4.3(s, 2H), 4.6(d, 1H), 4.7(s, 2H), 5.1(q, 1H),6.9(m 4H), 7.1(m, 2H), 7.4(m, 7H).

EXAMPLE 114-138

The same procedures as in Example 50 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(10mg, 26.4 μmol), correspondent acylchloride(39.6 μmol) andtriethylamine(20 μl, 142.6 μmol) to give the following titled compound.

EXAMPLE 1145,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-acetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 6H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 5H), 7.1(m, 1H), 7.5(m, 2H).

EXAMPLE 1155,6-dimethyl-2-(4-fluorophenylatnino)-4-{1-methyl-7-ethylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.2(t, 3H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.6(m, 3H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 2H).

EXAMPLE 1165,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-isopropylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.3(m, 6H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 2H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 6H), 7.5(m, 2H).

EXAMPLE 1175,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-butylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR (CDCl₃): 1.0(m, 3H), 1.5(m, 5H), 1.7(m, 2H), 2.1(s, 3H), 2.3(s, 3H),2.6(t, 2H), 2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H),6.9(m 4H), 7.1(m, 1H), 7.5(m, 2H).

EXAMPLE 1185,6-dimethy1-2-(4-fluorophenylamino)-4-(1-methyl-7-cyclopropylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.0(m, 2H), 1.2(m, 2H), 1.5(d, 3H), 1.8(m, 1H), 2.1(s, 3H),2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H),6.9(m, 6H), 7.5(m, 2H).

EXAMPLE 1195,6dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-cyclobutylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.0(m, 2H), 2.1(s, 3H), 2.3(m, 7H), 2.7(m, 1H),3.1(m, 1H), 3.4(m, 2H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 2H).

EXAMPLE 1205,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-cyclohexylcarbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.3(m, 6H), 1.5(d, 3H), 1.7(m, 4H), 2.1(s, 3H), 2.3(s, 3H),2.6(m, 1H), 2.7(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H),7.0(m, 5H), 7.5(m, 2H), 7.8(s, 1H).

EXAMPLE 1215,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(2-ethoxycarbonyletbyl)carbonyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.2(t, 3H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 3H),2.9(m, 2H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 4.2(q, 2H), 5.1(q, 1H),6.9(m, 6H), 7.5(m, 2H).

EXAMPLE 1225,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-benzoyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 5H), 7.2(d, 1H), 7.5(m, 5H),8.2(d, 2H).

EXAMPLE 123 5,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(4-methylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.5(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.1(m, 1H),7.3(m, 1H), 7.4(m, 2H), 8.1(m, 2H).

EXAMPLE 1245,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(4-propylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.0(t, 3H), 1.5(d, 3H), 1.7(m, 2H), 2.1(s, 3H), 2.3(s, 3H),2.7(m, 3H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 5H),7.1(m, 1H), 7.3(m, 2H), 7.5(m, 2H), 8.1(m, 2H).

EXAMPLE 1255,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(4-pentylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 0.9(t, 3H), 1.3(m, 6H), 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H),2.7(m, 3H), 3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H),7.2(m, 1H), 7.3(m, 1H), 7.5(m, 2H), 8.1(m, 2H).

EXAMPLE 1265,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(2-chlorobenzoyioxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 5H), 8.0(d, 1H).

EXAMPLE 1275,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(3-fluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 4H), 7.9(d, 1H),8.0(d, 1H).

EXAMPLE 128 5,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(3-trifluoromethylbenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 7.0(m, 5H), 7.2(t, 1H), 7.5(m, 2H),7.7(t, 1H), 7.9(d, 1H), 8.4(d, 1H), 8.5(s, 1H).

EXAMPLE 1295,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(2,3-difluorobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 4H), 7.9(t, 1H).

EXAMPLE 1305,6dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-(3-methoxyphenyl)acetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.8(m, 6H), 5.1(q, 1H), 6.9(m, 10H), 7.5(m, 2H).

EXAMPLE 1315,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(4-methoxyphenyl)acetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.8(m, 6H), 5.1(q, 1H), 6.9(m, 10H), 7.5(m, 2H).

EXAMPLE 1325,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(4-nitrobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl3): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 6H), 7.5(m, 2H), 8.4(s, 4H).

EXAMPLE 1335,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(3-cyanobenzoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.9(m, 5H), 7.2(d, 2H), 7.4(m, 2H),7.7(t, 1H), 7.9(d, 1H), 8.4(m, 2H).

EXAMPLE 1345,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(1-naphthoyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q 1H), 6.9(m, 6H), 7.5(m, 5H), 7.9(d, 1H),8.1(d, 1H), 8.5(d, 1H), 9.0(d, 1H).

EXAMPLE 1355,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-cinnamoyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.6(d, 1H), 6:9(m, 5H), 7.1(d, 1H),7.4(m, 4H), 7.6(m, 211), 7.9(d, 1H).

EXAMPLE 1365,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-crotonyloxy-1,2,3,4-tetrahydroissoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.0(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 5.1(q, 1H), 6.0(d, 1H), 6.9(m, 4H),2H), 7.5(m, 2H).

EXAMPLE 1375,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(thiophen-2-yl-acetoxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 4.1(s, 2H), 5.1(q, 1H), 6.9(m, 9H), 7.5(m, 2H).

EXAMPLE 1385,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-benzyloxyacetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(d, 2H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 4.4(s, 2H), 4.6(d, 1H), 4.7(s, 2H), 5.1(q, 1H),6.9(m, 2H), 7.1(m, 3H), 7.4(m, 8H).

EXAMPLE 1395-methyl-6-(N-t-butoxycarbonyl-glycyloxymetyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),N-t-butoxycarbonylglycine(27.8 mg, 0.158 mmol) and triethylamine(23.9 μl0.171 mmol) were added to a suspension of5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol) in anhydrous methylene chloride(1 ml). The reactionmixture was stirred for 1 day at room temperature, washed with water.The separated organic layer was concentrated and the residual oil waspurified by a silica gel column chromatography (dichloromethane/methanol20/1) to give the titled compound.

NMR(CDCl₃): 1.4(s, 9H), 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.1(m, 1H),3.5(m, 1H), 4.0(m, 3H), 5.1(s, 2H), 5.2(q, 1H), 6.9(m, 2H), 7.1(m, 5H),(m, 2H).

EXAMPLE 140-146

The same procedures as in Example 139 were repeated using5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole (26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),correspondent N-t-butoxycarbonylamino acid (0.158 mmol) andtriethylamine (23.9 μl, 0.171 mmol) to obtain the following titledcompound.

EXAMPLE 1405-methyl-6-(N-t-butoxycarbonyl-valyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 0.9(d, 3H), 1.0(d, 3H), 1.4(s, 9H), 1.5(d, 3H), 2.2(s, 3H),2.3(m, 1H), 2.8(m, 1H), 3.1(m, 1H), 3.5(m, 1H), 4.0(m, 1H), 4.2(m, 1H),5.1(m, 3H), 6.9(m, 2H), 7.1(m, 5H), 7.4(m, 2H).

EXAMPLE 1415-methyl-6-(N-t-butoxycarbonyl-O-benzylseryloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.4(s, 9H), 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.1(m, 1H),3.5(m, 1H), 4.0(m, 2H), 4.5(s, 2H), 4.6(m, 1H), 5.1(s, 3H), 5.5(d, 1H),2H), 7.1(m, 5H), 7.2(m, 5H), 7.4(m, 2H).

EXAMPLE 1425-methyl-6-(N-t-butoxycarbonyl-methionyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.4(s, 9H), 1.5(d, 3H), 2.1(s, 3H), 2.2(s, 3H), 2.8(m, 3H),3.1(m, 1H), 3.5(m, 1H), 4.0(m, 1H), 4.6(m, 1H), 5.1(m, 3H), 6.9(m, 2H),7.1(m, 5H), 7.4(m, 2H).

EXAMPLE 1435-methyl-6-(N-t-butoxycarbonyl-O-benzyl-aspartyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.4(s, 9H), 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.1(m, 3H),3.5(m, 1H), 4.0(m, 1H), 4.8(m, 1H), 5.1(s, 5H), 5.6(d, 1H), 6.9(m, 2H),7.1(m, 5H), 7.3(m, 5H), 7.4(m, 2H).

EXAMPLE 1445-methyl-6-(N-t-butoxycarbonyl-Im-benzyl-histidyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.4(s, 9H), 1.5(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.1(m, 3H),3.5(m, 1H), 4.0(m, 1H), 4.7(m, 1H), 4.9(s, 2H), 5.1(m, 3H), 6.0(d, 1H),6.6(s, 1H), 6.9(m, 2H), 7.1(m, 5H), 7.3(m, 5H), 7.4(s, 1H), 7.5(m, 2H).

EXAMPLE 1455-methyl-6-(N-t-butoxycarbonyl-phenylalanyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.4(s, 9H), 1.5(d, 3H), 2.1(s, 3H), 2.8(m, 1H), 3.1(m, 3H),3.5(m, 1H), 4.0(m, 1H), 4.7(m, 1H), 5.1(m, 3H), 6.9(m, 2H), 7.2(m, 10H),7.5(m, 2H).

EXAMPLE 1465-methyl-6-(N-t-butoxycarbonyl-prolyloxymethyl)-2-(4-fluorophenylatnino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.4(m, 11H), 1.5(d, 3H), 2.0(m, 2H), 2.2(d, 3H), 2.8(m, 1H),3.1(m, 1H), 3.5(m, 3H), 4.0(m, 1H), 4.4(m, 1H), 5.1(m, 3H), 6.8(s, 1H),6.9(m, 2H), 7.1(m, 5H), 7.5(m, 2H).

EXAMPLE 147-156

The same procedures as in Example 139 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl1-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),correspondent N-t-butoxycarbonylamino acid(0.158 mmol) and triethylamine(23.9 μl, 0.171 mmol) to obtain the following titled compound.

EXAMPLE 1475,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(N-t-butoxycarbonylglycyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5 (m, 12H), 2.1 (s, 3H), 2.3 (s, 3H), 2.7 (m, 1H), 3.1 (m,1H), 3.5 (m, 1H), 3.9 (m, 1H), 4.1 (d, 2H), 5.1 (m, 2H), 6.9 (m, 4H),7.1 (d, 1H), 7.4 (m, 2H).

EXAMPLE 1485,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(N-t-butoxycarbonyl-valyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.0 (m, 6H), 1.5 (m, 12H), 2.1 (s, 3H), 2.3 (s, 3H), 2.7 (m,1H), 3.1 (m, 1H), 3.5 (m, 1H), 3.9 (m, 1H), 4.4 (m, 1H), 5.1 (m, 2H),6.9 (m, 4H), 7.1 (d, 11H), 7.5 (m, 2H).

EXAMPLE 1495,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(N-t-butoxycarbonyl-O-benzyl-seryloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5 (m, 12H), 2.1 (s, 3H), 2.3 (s, 3H), 2.7 (m, 1H), 3.1 (m,1H), 3.5 (m, 1H), 3.8 (m, 1H), 4.0 (m, 2H), 4.6 (m, 2H), 5.1 (q, 1H),5.5 (d, 1H), 6.9 (m, 4H), 7.1 (d, 1H), 7.3 (m, 5H), 7.4 (m, 2H).

EXAMPLE 1505,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(N-t-butoxycarbonyl-methionyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5 (m, 12H), 2.1 (m, 6H), 2.3 (s, 3H), 2.6 (m, 3H), 3.1 (m,1H), 3.5 (m, 1H), 3.9 (m, 1H), 4.6 (m, 1H), 5.1 (m, 2H), 6.9 (m, 4H),7.1 (d, 1H), 7.4 (m, 2H).

EXAMPLE 151 5,6dimethyl-2-(4-fluorophenylamino)-4-{11-methyl-6-(N-t-butoxycarbonyl-O-benzyl-aspartyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5 (m, 12H), 2.1 (s, 3H), 2.3 (s, 3H), 2.7 (m, 1H), 3.1 (m,3H), 3.5 (m, 1H), 3.9 (m, 1H), 4.8 (m, 1H), 5.1 (m, 3H), 5.6 (d, 1H),6.9 (m, 4H), 7.1 (d, 1H), 7.3 (m, 5H), 7.5 (m, 2H).

EXAMPLE 152 5,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(N-t-butoxycarbonyt-asparaginyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5 (m, 12H), 2.1 (s, 3H), 2.3 (s, 3H), 2.7 (m, 1H), 3.0 (m,3H), 3.5 (m, 1H), 4.1 (m, 1H), 4.3 (m, 1H), 5.1 (q, 1H), 6.0 (d, 1H),6.6 (s, 1H), 6.7 (m, 1H), 6.9 (m, 3H), 7.4 (m, 2H).

EXAMPLE 1535,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(N-t-butoxycarbonyl-glutaminyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5 (m, 12H), 2.1 (m, 5H), 2.3 (s, 3H), 2.6 (m, 3H), 3.0 (m,1H), 3.5 (m, 11H), 3.9 (m, 1H), 4.3 (m, 1H), 5.0 (q, 1H), 6.6 (m, 2H),6.9 (m, 3H), 7.4 (m, 2H).

EXAMPLE 1545,6dimethyl-2-(4-fluorophenylamino)-4-{1-(-methyl-6-(N-t-butoxycarbonyi-Im-benzyl-histidyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 3H),3.5(m, 1H), 3.9(m, 1H), 4.8(m, 1H), 5.0(m, 3H), 6.2(m, 1H), 6.8(m, 2H),6.9(m, 4H), 7.1 (m, 1H), 7.3(m, 3H), 7.4(m, 3H).

EXAMPLE 1555,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(N-t-butoxycarbonyl-phenylalanyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.4(s, 9H), 1.5(m, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 3H), 3.5(m, 1H), 3.⁹(m, 1H), 4.8(m, 1H), 5.1(m, 2H), 6.8(m, 2H),7.0(m, 2H), 7.2(m, 6H), 7.5(m, 2H).

EXAMPLE 1565,6dimethyl-2-(4-fluorophenylarnino)-4-{1-methyl-6-(N-t-butoxycarbonyl-prolyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.0(m, 4H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 3H), 3.9(m, 1H), 4.5(m, 1H), 5.1(q, 1H), 6.9(m, 4H),7.1(m, 1H), 7.5(m, 2H).

EXAMPLE 157-166

The same procedures as in Example 139 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171 mmol),correspondent N-t-butoxycarbonylamino acid(0.158 mmol), andtriethylamine(23.9 μl, 0.171 mmol) to obtain the following titledcompound.

EXAMPLE 1575,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonylglycyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 4.2(d, 2H), 5.1(q, 1H), 5.2(t, 1H), 6.9(m, 4H),7.1(d 1H), 7.4(m, 2H).

EXAMPLE 1585,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-valyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.1(m, 6H), 1.5(m, 12H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 1H), 3.9(m, 1H), 4.5(m, 1H), 5.1(q, 1H), 5.2(t, 1H),6.9(m, 4H), 7.1(d, 1H), 7.5(m, 2H).

EXAMPLE 1595,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-O-benzyl-seryloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 1H),3.5(m, 1H), 3.8(m, 2H), 4.1(m, 1H), 4.6(m, 2H), 4.7(m, 1H), 5.0(q, 1H),5.5(d, 1H), 6.9(m, 5H), 7.3(m, 5H), 7.4(m, 2H).

EXAMPLE 1605,6dimethyl-2-(4-fluorophenylarnino)-4-{1-methyl-7-(N-t-butoxycarbonyl-methionyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.1(m, 6H), 2.3(s, 3H), 2.6(m, 3H), 3.1(m, 1H),3.5(m, 1H), 3.9(m, 1H), 4.6(m, 1H), 5.1(m, 2H), 6.9(m, 4H), 7.1(d, 1H),7.4(m, 2H).

EXAMPLE 1615,6-dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-O-benzyl-aspartyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 3H),3.5(m, 1H), 3.9(m, 1H), 4.8(m, 1H), 5.1(m, 3H), 5.6(d, 1H), 6.9(m, 5H),7.3(m, 5H), 7.5(m, 2H).

EXAMPLE 1625,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-asparaginyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.1(s, 3H), 2.3(s, 3H), 2.6(m, 1H), 3.0(m, 3H),3.5(m, 1H), 4.1(m, 1H), 4.3(m, 1H), 5.1(q, 1H), 6.0(d, 1H), 6.6(s, 1H),6.7(m 1H), 6.9(m, 3H), 7.4(m, 2H).

EXAMPLE 1635,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-glutamninyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl3): 1.5(m, 12H), 2.1(m, 5H), 2.3(s, 3H), 2.6(m, 3H), 3.0(m, 1H),3.5(m, 1H), 4.1(m, 2H), 5.1(q, 1H), 6.6(s, 1H), 6.7(d, 1H), 6.9(m, 3H),2H).

EXAMPLE 1645,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-Im-benzyl-histidyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H), 3.1(m, 3H),3.5(m, 1H), 3.9(m, 1H), 4.8(m, 1H), 5.0(m, 3H), 6.9(m, 8H), 7.3(m, 3H),7.4(m, 3H).

EXAMPLE 1655,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-phenylalanyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.4(s, 9H), 1.5(m, 3H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.2(m, 2H), 3.5(m, 1H), 3.9(m, 1H), 4.8(m, 1H), 5.1(m, 2H),6.6(m, 2H), 6.9(m, 2H), 7.2(m, 6H), 7.5(m, 2H).

EXAMPLE 1665,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(N-t-butoxycarbonyl-prolyloxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine

NMR(CDCl₃): 1.5(m, 12H), 2.0(m, 4H), 2.1(s, 3H), 2.3(s, 3H), 2.7(m, 1H),3.1(m, 1H), 3.5(m, 3H), 3.9(m, 1H), 4.5(m, 1H), 5.1(q, 1H), 6.6(m, 1H),6.9(m, 4H), 7.4(m, 2H).

EXAMPLE 1675,6dimethyl-2-(4-fluoropheniylamino)-4-(1-methyl-6-valyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylarnino-propyl) carbodiimide (32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-valine (34.4 mg, 0.158 mmol), and triethylamine(23.9 μl, 0.171 mmol) were added to a suspension of5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine(50mg, 0.132 mmol) in anhydrous methylene chloride (1 ml). The reactionmixture was stirred for 1 day at room temperature and washed with water.The separated organic layer was concentrated and the residual oil waspurified by a silica gel column chromatography (dichloromethane/methanol20/1). After evaporating of the solvent, the residual oil was dissolvedin 3M hydrochloride-ethylacetate solution, stirred for 2 hours at roomtemperature and concentrated. The resulting white solid was suspended inethyl ether and filtered to give the titled compound.

NMR(DMSO-d6): 1.0(m, 6H), 1.6(d, 3H), 2.2(s, 3H), 2.4(m, 4H), 2.9(m,1H), 3.1(m, 1H), 3.6(m, 1H), 4.2(m, 2H), 5.4(m, 1H), 7.0(m, 2H), 7.3(m,3H), 7.6(m, 2H), 8.8(m, 2H), 10.2(s, 1H).

EXAMPLE 1685,6dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-phenylalanyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procedures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-phenylalanine(42.0 mg, 0.158 mmol), andtriethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.

NMR(DMSO-d6): 1.6(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.8(m, 1H), 3.1(m,1H), 3.2(d, 2H), 3.6(m, 1H), 4.2(m, 1H), 4.5(m, 1H), 5.4(m, 1H), 6.8(m,2H), 7.3(m, 8H), 7.6(m, 2H), 9.0(m, 2H), 10.2(s, 1H).

EXAMPLE. 1695,6dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-valyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procedures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-valine (34.4 mg, 0.158 mmol), and triethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.

NMR(DMSO-d6): 1.0(m, 6H), 1.6(d, 3H), 2.2(s, 3H), 2.4(m, 4H), 2.9(m,1H), 3.1(m, 1H), 3.6(m, 1H), 4.2(m, 2H), 5.4(m, 1H), 7.0(m, 2H), 7.3(m,3H), 7.6(m, 2H), 8.9(m, 2H), 10.3(s, 1H).

EXAMPLE 1705,6dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-phenylalanyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procedures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-ylpyrimidine(SOmg, 0.132mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171mmol), N-t-butyloxycarbonyl-phenylalanine (42.0 mg, 0.158 mmol), andtriethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.

NMR(DMSO-d6): 1.5(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.8(m, 1H), 3.1(m,1H), 3.2(d, 2H), 3.6(m, 1H), 4.2(m, 1H), 4.5(m, 1H), 5.3(m, 1H), 6.8(m,2H), 7.3(m, 8H), 7.6(m, 2H), 9.0(m, 2H), 10.2(s, 1H).

EXAMPLE 1715-methyl-6-valyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedibydrochloride

The same procedures as in Example 167 were repeated using5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-valine (34.4 mg, 0.158 mmol), andtriethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.

NMR(DMSO-d6): 1.0(d, 6H), 1.6(d, 3H), 2.2(s, 3H), 2.3(m, 1H), 2.8(m,1H), 3.2(m, 1H), 3.6(m, 1H), 4.2(m, 2H), 5.4(m, 3H), 7.2(m, 6H), 7.6(m,2H), 8.8(m, 2H), 10.8(bs, 1H).

EXAMPLE 1725-methyl-6-(phenylalanyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procedures as in Example 167 were repeated using5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-phenylalanine (42.0 mg, 0.158 mmol), andtriethyl-amine (23.9 μl, 0.171 mmol) to afford the titled compound.

NMR(DMSO-d6): 1.6(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.3(d, 2H)3.6(m, 1H), 4.2(m, 1H), 4.6(m, 1H), 5.4(m, 3H), 7.2(m, 1H), 7.6(m, 2H),8.8(m, 211), 10.8(bs, 1H).

EXAMPLE 1735-acetoxymethyl-6-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

Acetylchloride (2.71 μ1, 39.6 μmol) and triethylamine (20 μl, 142.6μmol) were added to a suspension of5-hydroxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)pyrimidine(10 mg, 26.4 μmol) in dichloromethane(1 ml) and stirred for 1 day at aroom temperature. The reaction mixture was purified by a silica gelcolumn chromatography (ethylacetate/n-hexane=1/1) to give the titledcompound.

NMR (CDCl₃): 1.6(d, 3H), 2.2 (s, 3H), 2.4(s, 3H), 2.8(m, 1H), 3.2(m,1H), 3.6(m, 1H), 4.2(m, 1H), 4.6 (q, 2H), 5.4(q, 1H), 6.9(m, 3H), 7.2(m,4H), 7.5(m, 2H).

EXAMPLE 1745-valyloxymethyl-6-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5-hydroxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)pyrimidine(50 mg, 0.1 32 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.1 98 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-valine (34.4 mg, 0.158 mmol), andtriethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.

NMR (DMSO-d₆): 1.0 (d, 6H), 1.6 (d, 3H), 2.4 (s, 3H), 2.3 (m, 1H), 2.8(m, 1H), 3.2 (m, 1H), 3.6 (m, 1H), 4.2 (m, 2H), 5.4 (m, 3H), 7.2 (m,6H), 7.6 (m, 2H), 8.8 (m, 2H), 10.8(br, 1H).

EXAMPLE 1755-methyl-6-(4-morpholineacetoxymethyl)-2-(4-fluorophenylamino)-4-(t1-methyl-1,2,3,4tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrinidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),4-morpholineacetic acid hydrochloride(28.8 mg, 0.158 mmol), andtriethylamine(46 μl, 0.330 mmol) to afford the titled compound.

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 5H), 3.5(m, 1H),3.8(s, 4H), 4.1(s, 2H), 4.2(m, 1H), 5.2(m, 3H), 7.0(m, 6H), 7.5(m, 2H),11.0(s, 31H).

EXAMPLE 1765,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-morpholineacetoxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),4-morpholineacetic acid hydrochloride (28.8 mg, 0.158 mmol), andtriethylamine (46 μl, 0.330 mmol) to afford the titled compound.

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.7(m, 4H), 2.8(m, 1H)3.2(m, 1H), 3.5(m, 3H), 3.8(m, 4H), 4.2(m, 1H), 5.3(m, 1H), 7.0(m, 5H),7.5(m, 2H), 10.6(s, 1H), 14(bs, 1H).

EXAMPLE 1775,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(4-morpholineacetoxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),4-morpholineacetic acid hydrochloride(28.8 mg, 0.158 mmol), andtriethylamine(46 μl, 0.330 mmol) to afford the titled compound.

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.8(m, 1H), 3.0(s, 4H),3.2(m, 1H), 3.5(m, 1H), 3.7(m, 4H), 3.9(m, 4H), 4.2(m, 1H), 5.3(m, 1H),7.0(m, 5H), 7.5(m, 2H), 10.2(s, 1H).

EXAMPLE 1785-methyl-6-(4-benzylpiperazine)acetoxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinetrihydrochloride

The same procudures as in Example 167 were repeated using5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),4-benzylpiperazineacetic acid dihydrochloride (48.7 mg, 0.158 mmol), andtriethylamine(64 μl, 0.462 mmol) to afford the titled compound.

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 1H), 3.3(m, 8H)3.5(m, 1H), 4.0(s, 2H), 4.2(m, 3H), 5.2(m, 3H), 7.0(m, 7H), 7.5(m, 6H)11.0(d, 1H).

EXAMPLE 1795,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(4-benzylpiperazine)acetoxy-1,2,3,4tetrahydroisoquinolin-2-yl}pyrimnidinetrihydrochioride

The same procudures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy1,2,3,4-tetrahydroisoquinolin-2-ylppyrimidine(50 mg, 0.132 mmol ),1-hydroxybenzotriazole(26.8 mg, 0.1 98 mmol),-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mol),4-benzylpiperazinoacetic acid dihydrochyoride (48.7 mg, 0.158mmol), andtriethylamine(64 μl, 0.462mmol) to afford the titled compound.

NMR(CDCl ₃): 1.6(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.7(m, 9H), 3.1(m, 1H),3.5(m, 3H), 3.6(s, 2H), 4.0(m, 1H), 5.2(m, 1H), 6.9(m, 5H), 7.3(m, 5H)7.5(m, 2H), 8.9(bs, 1H).

EXAMPLE 1805,6dimethyl-2-(4-fluorophenylamino)-4-{(1-methyl-7-(4-benzylpiperazine)acetoxy1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine trihydrochioride

The same procudures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4{(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),4-benzyd piperazinoacetic acid dihydrochtoride (48.7 mg, 0.158 mmol),and triethylamine(64 μl, 0.462 mmol) to afford the titled compound.

NMR(CDCl₃): 1.6(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.8(m, 9H), 3.1(m, 1H)3.5(m, 3H), 3.8(s, 2H), 4.2(m, 1H), 5.2(m, 1H), 6.9(m, 5H), 7.4(m, 7H),10.1(bs, 1H).

EXAMPLE 1815-rethyl-6-(1-piperidineacetoxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoli-2-yl)pyrimiidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimnide(32.9 mg, 0.171 mmol),piperidineacetic acid hydrochloride (28.5 mg, 0.158 mmol), andtriethylamne(46 μl, 0.330 mmol) to afford the titled compound.

NMR(CDCl₃): 1.6(d, 3H), 1.9(m, 6H), 2.2(s, 3H), 2.8(m, 1H), 3.1(m, 1H),3.2(m, 4H), 3.5(m, 1H), 4.2(m, 3H), 5.2(m, 3H), 6.9(m, 2H), 7.2(m, 4H),7.5(m, 2H), 10.2(bs, 1H).

EXAMPLE 1825,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-6-(1-piperidineacetoxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),1-piperidineacetic acid hydrochloride (28.5 mg, 0.158 mmol), andtriethylamine(46 μl, 0.330 mmol) to afford the titled compound.

NMR(CDCl₃): 1.5(m, 9H), 2.2(s, 3H), 2.4(s, 3H), 2.6(m, 4H), 2.8(m, 1H)3.1(m, 1H), 3.5(m, 3H), 4.0(m, 1H), 5.2(m, 1H), 7.0(m, 5H), 7.5(m, 2H),8.5(bs, 1H).

EXAMPLE 1835,6dimethyl-2-(4-fluorophenylamino)-4-{1-methyl-7-(1-piperidinoacetoxy)-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5,6-dimethyl-2-(4-fluorophenylamino)-4(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50mg, 0.1 32 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol)1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.17 mmol),1-piperidineacetic acid hydrochloride(28.5 mg, 0.15 8 mmol), andtriethylamine(46 μl, 0.330 mmol) to afford the titled compound.

NMR(CDCl₃): 1.5(m, 9H), 2.2(s, 3H), 2.4(s, 3H), 2.6(m, 4H), 2.8(m, 1H),3.1(m, 1H), 3.5(m, 3H), 4.1(m, 1H), 5.2(m, 1H), 7.0(m, 5H), 7.5(m, 2H),9.9(bs, 1H).

EXAMPLE 1845,6dimethyl-2-(4-fluoro-2-valyfoxyphenylamino)-4-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procudures as in Example 167 were repeated using5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluoro-2-hydroxyphenylamino)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-valine(34.4 mg, 0.158mmol), and triethylamine(23.9μl, 0.171 mmol) to afford the titled compound.

NMR (DMSO-d₆): 1.0 (m, 6H), 1.6 (d, 3H), 2.2 (s, 3H), 2.4 (m, 4H), 2.9(m, 1H), 3.1 (m, 1H), 3.6 (m, 1H), 4.2 (m, 1H), 4.6 (m, 1H), 5.4 (m,1H), 7.2 (m, 5H), 7.6 (m, 2H), 8.9 (m, 2H).

EXAMPLE 1855,6dimethyl-2-(4-fluoro-2-phenylalanyloxyphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinedihydrochloride

The same procedures as in Example 167 were repeated using5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluoro-2-hydroxyphenylamino)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol),1-ethyl-3-(3-dimethylamninopropyl)carbodiimide(32.9 mg, 0.171 mmol),N-t-butyloxycarbonyl-phenylalanine(42.0 mg, 0.158 mmol), andtriethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.

NMR (DMSO-d₆): 1.5 (d, 3H), 2.2 (s, 3H), 2.4 (s, 3H), 2.8 (m, 1H), 3.1(m, 3H), 3.6 (m, 1H), 4.2 (m, 1H), 5.0 (m, 1H), 5.4 (m, 1H), 6.8 (m,2H), 7.2 (m, 10H), 9.0 (m, 2H).

EXAMPLE 186

2-(4-Fluorophenylamino)-5-methoxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidinehydrochloride

2-(4-Fluorophenylamino)-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquino-line-2-yl)pyrimidine(0.9 g, 2.58 mmol) was added to chloromethyl methyl ether (3 ml) in asealed tube. The mixture was stirred at 80° C. for 1 day. After coolingto room temperature, ethyl ether was added to mixture. Resulting solidwas removed by filtration. Filtrate was washed with aqueous 2N NaOHsolution, dried over sodium sulfate, and concentrated under reducedpressure. Crude product was purified with a silica gel columnchromatography (eluent: ethyl acttate:hexane=1:3). Purified compound wastreated with HCl solution in ethyl ether. Precipitated solid wasisolated by filtration, washed with ethyl ether, and dried in vacuum. Itgave 0.6 mg of the titled compound.

Yield: 0.05%; NMR (CDCl3): 8 1.6(d, 3H), 2.4(s, 3H), 2.8(m, 1H), 3.2(m,1H), 3.5(s, 3H), 3.6(m, 1H), 4.2(m, 3H), 5.4(q, 1H), 6.9(m, 2H), 7.1(m,4H), 7.5(m, 2H).

Test 1: Inhibition of proton pump (H⁺/K⁺-ATPase activity)

A proton pump enzyme was prepared by the same method as in theExperiment 1-1 of WO 94/14795. Further, the inhibitory effect of protonpump activity was measured by the same method as in Experiment 1-2 of WO94/14795.

Namely, the proton pump activity stimulated by Mg⁺⁺ was used as anegative comparative group, and the activity stimulated by Mg⁺⁺ and K⁺was used as a positive comparative group. The comparative compound wasomeprazole.

Test tubes were divided into 4 groups: Group 1 as negative comparativegroup(n=3), Group 2 as positive comparative group(n=3), Group 3(n=5×2)to be administered with the compound of the present invention and Group4(n=5×2) to be administered with the comparative compound.

The inhibitory effects of Groups 3 and 4 on proton pump activity weremeasured by employing the compound prepared in Examples and omeprazole,respectively, each of which was dissolved in dimethylsulfoxide at 5different concentrations.

To each of Groups 1, 2, 3 and 4 were added 100 μl of magnesiumchloride(40 mM) dissolved in 40 mM Tris-HCI buffer(ph 6.0) and 100 μg ofthe enzyme source. The 50 μl of potassium chloride(50 mM) and 50 μl ofammonium chloride(6 mM) dissolved in 40 mM Tris-HCl buffer(pH 6.0) wereadded to all groups except for group 1.

10 μl of dimethylsulfoxide was added to each of Groups 1 and 2; and toGroup 3 was added 10 μl of dimethylsulfoxide solution prepared bydissolving compound of EXAMPLE at 5 different concentration(n=5×2). ToGroup 4, 10 μl of the solution prepared by dissolving omeprazole indimethylsulfoxide at 5 different concentration(37.6, 21.4, 12.2, 7.0 and4.0 μM) was added(n=5×2). 40 mM Tris-HCI buffer(pH=6.0) was addedthereto so as to make the total volume 400 μl.

Thereafter, the test tube of each Group were placed at 37° C. for 30minutes for the preincubation. 100 μl ATP solution (6.6 mM) was addeduntil the reaction volume became 500 μl. After the reaction was carriedout at 37° C. for 30 minutes, 25% cold trichloroacetic acid was added toterminate the enzyme reaction. The released inorganic phosphate wasmeasured by an automatic analyzer(Express 550, coming).

The difference between Group 1 and Group 2 represents the proton pumpactivity activated by K⁺ only. The IC₅₀s of Group 3 and 4 werecalculated from Litchfield-wilcoxon equation[see, e.g., J. Pharrnacol.Exp. Ther., 96, 99(1949)]. The concentrations of the test compoundsinhibiting 50% of the proton pump activity are represented as IC₅₀ inTable 1.

TABLE 1 Test compound IC50 (μM) Effect ratio Example 2 7.85 1.4 Example5 6.91 1.6 Example 14 2.15 5.2 Example 22 6.69 1.7 Example 23 0.43 25.8Example 25 1.85 6.0 Example 26 2.60 4.3 Example 27 1.55 7.2 Example 281.74 6.4 Example 29 2.55 4.4 Example 31 2.56 4.3 Example 32 1.34 8.3Example 34 0.43 25.8 Example 36 0.31 35.8 Example 43 0.18 61.7Omeprazole 11.10 —

As shown in Table 1, the compounds of the present invention have anexcellent proton pump inhibitory activity over omeprazole.

Test 2: Inhibition of gastric secretion

In accordance with the method disclosed in Shay, H., et al.,Gastroenterology 5 43-61(1945), Test 2 was carried out.

Sprague-Dawly rats having a body weight of 170±10 g were divided into 3groups(n=5) and deprived of food for 24 hours before the experiment withfree access to water. Under ether anesthesia, the abdomen was incised,and the pylorus was ligated. As a comparative group, Group 1 wasadministered intraduodenally in a volume of 0.5 ml/200 g of 30% aqueouspolyethylene glycol 400 solution. Groups 2 and 3 were administeredintraduodenally with the compound of Example and omeprazole,respectively, each of which was suspended in 30% aqueous polyethyleneglycol 400 solution at a concentration of 20 mg/kg. After closing theabdominal cavity, the rats were placed for 5 hours and then killed bycervical dislocation. The stomach was extracted to obtain gastric juice.

Tne gastric juice was centrifuged at 1,000 g to remove precipitates. Theamount and acidity of the gastric juice were measured. Relative volumes,relative acid concentrations and relative acid outputs of the testcompounds were calculated from equations(I), (II) and (III) and theresults are shown in Table 2.

Relative volume=(the average amount of gastric juice of Group 1—theaverage amount of gastric juice of Group 2)/(the average amount ofgastric juice of Group 1−the average amount of gastric juice of Group3)—(I)

Relative acid concerntration=(the average acidity of Group 1—the averageacidity of Group 2)/(the average acidity of Group 1—the average acidityof Group 3)—(II)

Relative acid output (the total amount of acid output of Group 1—thetotal amount of acid output of Group 2)/(the total amount of acid outputof Group 1—the total amount of acid output of Group 3)—(m)

The results are shown in Table 2.

TABLE 2 Relative Relative Relative Test compound volume conc. AcidOutput Example 2 0.69 0.57 0.70 Example 5 0.45 0.18 0.43 Example 14 0.930.41 0.79 Example 22 0.59 0.46 0.62 Example 23 1.58 1.34 1.23 Example 251.00 0.52 0.86 Example 26 0.67 0.64 0.74 Example 27 0.99 0.68 0.90Example 28 0.78 0.60 0.78 Example 29 0.78 0.81 0.88 Example 31 1.06 0.971.01 Example 32 0.84 0.47 0.77 Example 34 0.81 0.45 0.78 Example 36 1.051.08 1.15 Example 50 1.01 0.77 0.98 Example 51 1.09 1.02 1.06 Example 520.86 0.88 0.96 Example 54 0.79 0.79 0.95 Example 74 1.57 1.02 1.25Example 107 0.62 0.56 0.73 Example 139 1.01 0.75 1.01 Example 144 0.900.80 0.94 Example 171 1.46 1.42 1.33 Example 172 1.48 1.33 1.34 Example175 0.87 0.30 0.79 Example 181 0.99 0.16 0.80

What is claimed is:
 1. Pyrimidine derivative of the following formula(I):

wherein B is C₃-C₇ cycloalkyl; C₁-C₃ alkoxyethyl; 1-naphthylmethyl,4-methylthiazol-2-yl or 4-phenylthiazol-2-yl or a group of formula (II):

wherein R₆ is hydrogen, methyl, hydroxy, methoxy, or a group of formula(III):

wherein Z is C₁-C₄ alkyl; C₂-C₄ alkenyl optionally substituted byphenyl; cycloalkyl; benzyloxyalkyl; alkoxycarbonylalkyl;morpholinomethyl; piperidinomethyl; 4-benzyl-piperazinomethyl; phenyloptionally mono- or polysubstituted by nitro, halogen, C₁-C₅ alkyl,C₁-C₄ alkoxy, cyano or trifluoromethyl; naphthyl; benzyl optionallysubstituted by alkoxy; thiophen-2-yl-methyl;1-alkoxycarbonyl-pyrrolidin-2-yl or —CHR₈NHR9, wherein R₈ is hydrogen,methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl,benzyloxycarbonylmethyl, carbamoylmethyl, carbamoylethyl, or1-benzylimidazol-4-ylmethyl and R₉ is hydrogen or t-butoxycarbonyl; andR₇ is hydrogen or halogen; R₁ is hydrogen, methyl, hydroxymethyl orC₁-C₃ alkoxymethyl, and R₂, R₃, R₄ and R₅ are respectively hydrogen,methyl, hydroxy, methoxy, or the group of formula (III) wherein Z is thesame as defined above; provided that when B is C₃-C₇ cycloalkyl, C₁-C₃alkoxyethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or4-phenylthiazol-2-yl, then R₁ is hydrogen or methyl, and R₂, R₃, R₄, andR₅ are hydrogen; when B is a group of formula (II) and R₁ ishydroxymethyl or C₁-C₃ alkoxymethyl, then R₂, R₃, R₄, R₅ and R₆ arehydrogen; and when B is a group of formula (II) and R₁ is hydrogen ormethyl, then one or two of R₂, R₃, R₄, R₅ and R₆ are hydroxy, methoxy,or a group of formula (III) and the others are hydrogen or methyl, orpharmaceutically acceptable salts thereof.
 2. The compound of claim 1,wherein B is C₃-C₇ cycloalkyl, C₁-C₃ alkoxyethyl, 1-naphthylmethyl,4-methylthiazol-2-yl or 4-phenylthiazol-2-yl.
 3. The compound of claim1, wherein B is a group of formula (II); R₁ is hydrogen or methyl; andone or two of R₂, R₃, R₄, R₅ and R₆ are hydroxy or methoxy.
 4. Thecompound of claim 1, wherein B is a group of formula (II); R₁ ishydrogen or methyl; and one or two of R₂, R₃, R₄, R₅ and R₆ are a groupof formula (III).
 5. The compound of claim 1, wherein B is a group offormula (II) and R₁ is hydroxymethyl or C₁-C₃ alkoxymethyl.
 6. Apharmaceutical composition for treating peptic ulcer which comprises atherapeutically effective amount of the pyrimidine derivative orpharmaceutically acceptable salt thereof defined in claim 1 togetherwith a conventionally pharmaceutically acceptable carrier.
 7. A methodfor treating peptic ulcer comprising administering to a subject in needof such treatment a pyrimidine derivative or pharmaceutically acceptablesalt thereof as defined in claim 1 in an amount effective for treatingpeptic ulcer.
 8. A method for treating peptic ulcer comprisingadministering to a subject in need of such treatment a pyrimidinederivative or pharmaceutically acceptable salt thereof as defined inclaim 2 in an amount effective for treating peptic ulcer.
 9. A methodfor treating peptic ulcer comprising administering to a subject in needof such treatment a pyrimidine derivative or pharmaceutically acceptablesalt thereof as defined in claim 3 in an amount effective for treatingpeptic ulcer.
 10. A method for treating peptic ulcer comprisingadministering to a subject in need of such treatment a pyrimidinederivative or pharmaceutically acceptable salt thereof as defined inclaim 4 in an amount effective for treating peptic ulcer.
 11. A methodfor treating peptic ulcer comprising administering to a subject in needof such treatment a pyrimidine derivative or pharmaceutically acceptablesalt thereof as defined in claim 5 in an amount effective for treatingpeptic ulcer.
 12. The compound of claim 1, wherein the pharmaceuticallyacceptable salt is an inorganic acid salt.
 13. The compound of claim 12,wherein the inorganic acid salt is selected from the group consisting ofhydrochloride, sulfate, phosphate and nitrate salts.
 14. The compound ofclaim 1, wherein the pharmaceutically acceptable salt is an organic acidsalt.
 15. The compound of claim 14, wherein the organic acid salt isselected from the group consisting of tartrate, fumarate, citrate,mesylate and acetate salts. 16.5,6-dimethyl-2-(2-methoxyethylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof. 17.6-hydroxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof. 18.5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof. 19.5-hydroxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)pyrimidineor a pharmaceutically acceptable salt thereof. 20.5-hydroxymethyl-6-methyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof. 21.5-methyl-6-(thiophen-2-yl-acetoxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof. 22.5-methyl-6-valyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof. 23.5-methyl-6-(phenylalanyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof. 24.5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidineor a pharmaceutically acceptable salt thereof.